Acknowledgment
First of all I can not give a word to fulfill my deepest
thanks to "Allah" the most gracious and the most merciful
for lighting me the way not only throughout this work but
also throughout my whole life.
I

would

like

to

express

my

deep

thanks,

and

everlasting gratitude to Prof. Badrya Abdel Haleem ElKastawy Professor of Anesthesiology & critical Care Tanta University, for here kind support, and supervision
throughout the entire work which gave me the valuable
opportunity to benefit from this contrast help and faithful
guidance.
I would also like to thank and express my extreme
indebtedness to Prof. Salama Ibrahim El-Hawary Professor
of Anesthesiology & critical Care - Tanta University, for his
constructive criticism, constant help, expert guidance and
very generous cooperation. I sincerely thank him for
revising the whole work, so that the final presentation of
this piece of work was achieved.
Also, I wish to express my gratitude and most sincere
thank to Dr. Reda Sobhi Salama Abdel Rahman Lecturer of
Anesthesiology & critical Care - Tanta University for his
support, help and encouragement.
In addition, I wish to thank every and each member
in the Department of Anesthesiology at the Faculty of
Medicine Tanta University who taught me and always
working

to

create

new

generations

of

competent

anesthetists.
Last but not least, I thank all my colleagues, the
nursing, and all who gave me hand while working on this
thesis.

Dedication
This work is dedicated to those who gave
meaning to my life
To my Father and Mother who gave me every
thing and took nothing
To my wife for her patience throughout this
work.
To LEEN, my beloved daughter, for being in
my life.
To my brother and my sister who occupy an
important space inside my heart.

Mohammad El-Kolaly
6/1/2011

Abstract
Background: Post-spinal shivering is very distressing for patients
and may induce a variety of complications. In this prospective
randomized, comparative, placebo controlled study, the efficacy of each
of midazolam, midazolam plus ketamine, tramadol, and tramadol plus
ketamine for prophylaxis of post-spinal shivering was evaluated and
compared to each other.
Methods: one hundred ASA status I and II patients between the
ages of 21- 60 years, who were undergoing elective orthopedic surgery
under spinal anesthesia, were randomly assigned to one of five groups;
Group C (n=20) received saline as a control. Group M (n=20) received
Midazolam 75 Âľg/kg. Group MK (n=20) received Midazolam 37.5
Âľg/kg plus Ketamine 0.25 mg/kg. Group T (n=20) received Tramadol
0.5 mg/kg. Group TK (n=20) received Tramadol 0.25 mg/kg plus
Ketamine 0.25 mg/kg. All of these drugs were diluted to volume of 5 ml
and was given as an I.V. bolus immediately after intrathecal injection.
Results: The incidences of shivering in Groups C, M, MK, T and
TK were 55%, 45%, 5%, 30% and 15% respectively (P-value was
0.003). The differences between Group MK and Groups C, M, and T
were statistically significant (P-value was < 0.001, 0.004 and 0.046
respectively) while the difference between Group MK and Group TK
was not significant (P-value was 0.302). Group TK also showed a
statistically significant lower incidence of shivering when compared to
Groups C and M (P-value was 0.009 and 0.041 respectively) but when
compared with Group T, the difference was not statistically significant
(P-value was 0.225). The incidence of shivering in Group T was less
than its incidence in Groups C and M but this was not statistically
significant (P-value was 0.100 and 0.257 respectively). The difference
between Groups C and M was not statistically significant (P-value was
0.376).
Conclusion: I.V. midazolam plus ketamine or Tramadol plus
Ketamine is better than Midazolam or Tramadol for prophylaxis of postspinal shivering. Whereas the midazolam plus ketamine is superior to
tramadol plus ketamine.

List of Abbreviations
5-HT

5-hyroxytryptamine

ASA

American Society of Anesthesiology

CBF

Cerebral blood flow

CMRO2

Cerebral metabolic rate for oxygen

CNS

Central nervous system

CSF

Cerebrospinal fluid

CVS

Cardiovascular system

ECG

Electrocardiogram

GABA

Îł-amino-butyric acid

HR

Heart rate

ICP

Intracranial pressure

IOP

Intraocular pressure

MAP

Mean arterial blood pressure

NMDA

N-methyl-D-aspartate

PDPH

Post-dural puncture headache

RR

Respiratory rate

SD

Standard Deviation

SpO2

Peripheral O2 saturation

Temp

Tympanic membrane temperature

i

List of Tables
Table

Title

Page

1

Dermatomal levels of spinal anesthesia for common surgical procedures

11

2

Drug selection for hyperbaric spinal Anesthesia

17

3

Factors That May Increase the Incidence of PDPH

20

4

Factors Not Increasing the Incidence of PDPH

20

5

Doses of Ketamine

57

6

Patients' demographic data, ASA status and duration of surgery

72

7

Changes of heart rate in Group C

73

8

Changes of heart rate in Group M

75

9

Changes of heart rate in Group MK

77

10

Changes of heart rate in Group T

79

11

Changes of heart rate in Group TK

81

12

Changes of the mean heart rate in the five groups

83

13

Changes of MAP in Group C

85

14

Changes of MAP in Group M

87

15

Changes of MAP in Group MK

89

16

Changes of MAP in Group T

91

17

Changes of MAP in Group TK

93

ii

18

Changes of the MAP in the five groups

95

19

Changes of reparatory rate in Group C

97

20

Changes of reparatory rate in Group M

99

21

Changes of reparatory rate in Group MK

101

22

Changes of reparatory rate in Group T

103

23

Changes of reparatory rate in Group TK

105

24

Changes of the respiratory rate in the five groups

107

25

Changes of SpO2 in Group C

109

26

Changes of SpO2 in Group M

111

27

Changes of SpO2 in Group MK

113

28

Changes of SpO2 in Group T

115

29

Changes of SpO2 in Group TK

117

30

Changes of the SpO2 in the five groups

119

31

Changes of tympanic membrane temperature in Group C

121

32

Changes of tympanic membrane temperature in Group M

123

33

Changes of tympanic membrane temperature in Group MK

125

34

Changes of tympanic membrane temperature in Group T

127

35

Changes of tympanic membrane temperature in Group TK

129

36

Changes of tympanic membrane temperature in the five groups

131

iii

37

Overall incidence of shivering in the five groups

134

38

Shivering score of all patients in the five groups

136

39

Incidence of severe shivering (score â&#x2030;Ľ 3) in the five groups

138

40

Incidence of complications in the five groups

140

41

Sedation score of all patients in the five groups

142

iv

List of Figures
Figure

Title

Page

1

Sagittal section through lumbar vertebrae

4

2

Arterial supply to the spinal cord [Cross-sectional view]

7

3

Spinal needles

13

4

Lateral decubitus position

13

5

Sitting position

14

6

Unintentional hypothermia during general anesthesia

25

7

Schematic diagram of the shivering pathway

26

8

Chemical structure of bupivacaine

40

9

Chemical structure of midazolam

45

10

Chemical structure of ketamine

51

11

Simulated time course of plasma levels of ketamine after an induction
dose of 2 mg/kg

heat production up to 600% after general or regional anesthesia(2).
Regional anesthesia is associated with post-anesthetic shivering in
up to 60% of patients

(3)

. Shivering may be normal thermoregulatory

mechanism in response to core hypothermia due to redistribution of heat
from core to periphery

(4)

. However, non- thermoregulatory shivering

also occurs in normothermic patients (5).
Post-anesthetic shivering may cause major discomfort to
patients(6), and aggravate wound pain by stretching incisions and increase
intracranial

(7)

and intraocular pressure (8). Shivering may increase tissue

oxygen demand by as much as 500% and accompanied by increases in
minute ventilation and cardiac output to maintain aerobic metabolism.
This may be deleterious in patients with impaired cardiovascular reserve
or a limited respiratory capacity(9). Shivering also may interfere with the
monitoring of patients by causing artifacts of the ECG, blood pressure,
and pulse oximetry recording (10).
Various opioid and non-opioid agents were used to prevent and
treat shivering, but they are not without side effects like hemodynamic
instability, respiratory depression, nausea and vomiting etc. A variety of
physical agents (radiant heat, space blanket, etc.) were also used to
prevent post-anesthetic shivering, but those were cumbersome and with
limited success (11).

Midazolam is one of the benzodiazepines. It was found that it may
decrease the incidence of shivering

(3)

. Ketamine which is a competitive

N-Methyl-D-Aspartate (NMDA) receptors antagonist, has been found to
be effective in preventing and treating post-anesthetic shivering via
central effects or via its effect on the hemodynamics of the
cardiovascular system (12, 13).

2

Review of literature

2010

Review of literature

Spinal Anesthesia
Spinal, caudal, and epidural blocks were first used for surgical
procedures at the turn of the twentieth century. These central blocks
were widely used prior to the 1940s until increasing reports of permanent
neurological injury appeared. However, a large-scale epidemiological
study conducted in the 1950s indicated that complications were rare
when these blocks were performed skillfully with attention to asepsis
and when newer, safer local anesthetics were used. A resurgence in the
use of central blocks ensued, and today they are once again widely used
in clinical practice. (14)

Functional Anatomy:
I) The vertebral column:
The vertebral column consists of 33 vertebrae: 7 cervical (C), 12
thoracic (T), 5 lumbar (L), 5 sacral (S), and 4 coccygeal (Co) vertebrae.
All of the vertebrae have the same basic shape, which is subject to
certain variations in the individual sections of the spine. The basic shape
consists of an anterior body and a dorsal vertebral arch, which consists of
pedicles and laminae. The laminae of the vertebral arch join dorsally to
form the spinous process. A transverse process branches off on each side
of the vertebral arch, as well as a superior and an inferior articular
process. The vertebral column usually contains three curves. The
cervical and lumbar curves are convex anteriorly, and the thoracic curve
is convex posteriorly. The vertebral canal (which provides excellent
protection for the spinal cord) and the spinal cord, with its meningeal
covering, extend throughout the whole length of the spine terminating in
the cauda equina. The spinal vessels and nerves emerge laterally through

3

Review of literature

openings at the upper and lower margins of the roots of the arches of the
adjoining vertebrae (the intervertebral foramina) (15)
II) The ligaments of the spinal column: (figure 1)
The anterior longitudinal ligament is attached at the anterior edge
of the vertebral bodies and intervertebral disks. The posterior
longitudinal ligament lies behind the vertebral bodies in the medullary
canal. The supraspinous ligaments extend from C7 to the sacrum along
the tips of the spinous processes, with which they are connected, and
they become thicker from cranial to caudal. The interspinous ligaments
connect the roots and tips of the spinous processes. The intertransverse
ligaments Serve to connect the transverse processes. The ligamentum
flavum connects the neighboring laminae. It is at its thinnest in the
midline, and its thickness increases laterally. The size and shape of the
ligamentum flavum vary at the various levels of the spine. (15)

Figure 1 : Sagittal section through lumbar vertebrae

4

(14)

Review of literature

III)The spinal cord:
Spinal cord is continuous cephalad with the brainstem through the
foramen magnum and terminates caudally in the conus medullaris.This
caudal termination, because of differential growth rates between the
bony vertebral canal and the central nervous system (CNS), varies from
L3 in infants to the lower border of L1 in adults (14).
IV) The spinal cord coverings: (figure 1):
a) The dura mater is the outermost layer. It is a randomly
organized fibroelastic membrane which is a direct extension of the
cranial dura mater and extends as the spinal dura mater from the foramen
magnum to S2, where the filum terminale (an extension of the pia mater
beginning at the conus medullaris) blends with the periosteum on the
coccyx. There is a potential space between the dura mater and the
arachnoid, the subdural space that contains only small amounts of serous
fluid and thus allows the dura and arachnoid to move over each other.
Surrounding the dura mater is the epidural space which contains the
nerve roots that traverse it from foramina to peripheral locations, as well
as fat, areolar tissue, lymphatics, and blood vessels. This space is the
target when performing epidural anesthesia or analgesia(14).
b) The arachnoid mater is the middle layer, and it is a delicate,
nonvascular membrane closely attached to the dura and ends also at S2.
It functions as the principal barrier to drugs crossing in and out of the
cerebrospinal fluid (CSF) and is estimated to account for 90% of the
resistance to drug migration(16).
c) The pia mater is a highly vascular membrane that closely
invests the spinal cord. It is continuous cranially with the pia of the brain
5

Review of literature

and caudally ends in the filum terminale, which helps to hold the spinal
cord to the sacrum. The space between the arachnoid and pia mater is
known as the subarachnoid space in which are the CSF, spinal nerves, a
trabecular network between the two membranes, and blood vessels that
supply the spinal cord and lateral extensions of the pia mater and dentate
ligaments, which provide lateral support from the spinal cord to the dura.
This space is the target when performing spinal anesthesia. Although the
spinal cord ends at the lower border of L1 in adults, the subarachnoid
space continues to S2(14).
V) The spinal cord Blood Supply:
a) Arterial supply: (figure 2)
The two posterolateral arteries arise from the vertebral
arteries and supply the posterior 1/3 of the cord.
The anterior spinal artery arises from the vertebral
arteries and supplies the anterior 2/3 of the cord.
The radicular arteries enter every intervertebral
foramen and supply the spinal nerve roots
The radiculospinal branches arise from the vertebral
arteries and the aorta. Of these, the largest is the artery
of Adamkiewicz. It supplies much of blood flow to
anterior spinal artery(14).

6

Review of literature

Figure 2: Arterial supply to the spinal cord [Cross-sectional view]

(14)

b) Venous drainage:
The venous drainage comprises a plexus of anterior and
posterior spinal veins that drain along the nerve roots through the
intervertebral foramina into the segmental veins; the vertebral
veins in the neck, the azygos veins in the thorax, lumbar veins in
the abdomen and lateral sacral veins in the pelvis. At the foramen
magnum, they communicate with the medullary veins (17).

stimuli, whereas motor blockade produces skeletal muscle relaxation.
Spinal nerve roots contain varying mixtures of nerve fiber types. Smaller
(in diameter) and myelinated fibers are generally more easily blocked
than larger and unmyelinated ones. This, and the fact that the
concentration of local anesthetic decreases with increasing distance from
the level of injection, explains the phenomenon of differential blockade.
Differential blockade typically results in sympathetic blockade that may
be two segments higher than the sensory block, which in turn is usually
two segments higher than the motor blockade

(14)

.

II) Autonomic Blockade:
a) Cardiovascular Effects of Spinal Anesthesia:
The sympathetic blockade produced by spinal anesthesia induces
hemodynamic changes. The block height determines the extent of
sympathetic blockade, which determines the amount of change in
cardiovascular parameters. However, this relationship cannot be
predicted.
Hypotension

occurs

in

about

33%of

the

non-obstetric

population(18). Arterial and venodilatation both occur in spinal anesthesia
and combine to produce hypotension. Arterial vasodilatation is not
maximal after spinal blockade as the vascular smooth muscle continues
to retain some autonomic tone after sympathetic denervation. Due to
retention of autonomic tone, total peripheral vascular resistance
decreases only by 15% to 18%, thus mean arterial pressure (MAP)
decreases by 15% to 18% if cardiac output is not decreased. In patients
with coronary artery disease, systemic vascular resistance can be
decreased by up to 33% after spinal anesthesia(19).

8

Review of literature

However, after spinal anesthesia, venodilatation will be maximal.
Venous return to the heart, or preload, therefore depends on patient
positioning during spinal anesthesia. Because preload determines cardiac
output and patient positioning is a major factor in determining preload,
as long as a euvolemic patient is positioned with the legs elevated above
the heart, there should be no significant changes in cardiac output after
spinal anesthesia. The reverse Trendelenburg position, however, leads to
large decreases in preload and thus large decreases in cardiac output(20).
Most patients do not experience a severe change in heart rate after
spinal anesthesia. The incidence of bradycardia in the non-obstetric
population is about 13%(18).The sympathetic cardiac accelerator fibers
emerge from the T1 to T4 spinal segments, and blockade of these fibers
is proposed as the cause of bradycardia. Another cause of bradycardia
may be the fall in right atrial filling, which decreases outflow from
intrinsic stretch receptors located in the right atrium and great veins(21).
Even though both of these mechanisms are proposed to cause
bradycardia, other undetermined factors may contribute to the
bradycardia seen with spinal anesthesia(22). Even though bradycardia is
usually well tolerated, asystole and second- and third-degree heart block
can occur, so it is wise to be vigilant when monitoring a patient after
spinal anesthesia and treat promptly and aggressively(23).
b) Respiratory Effects of Spinal Anesthesia:
Alterations in pulmonary variables in healthy patients during
neuraxial block are usually of little clinical consequence. Tidal volume
remains unchanged during high spinal anesthesia, and vital capacity
decreases a small amount. This is a result of a decrease in expiratory
9

Review of literature

reserve volume related to paralysis of the abdominal muscles necessary
for forced exhalation rather than a decrease in phrenic or diaphragmatic
function(24).
c) Gastrointestinal Effects of Spinal Anesthesia:
The sympathetic innervation to the abdominal organs arises from
T6 to L2. Sympathetic blockade and unopposed vagal activity cause
increased peristalsis of the gastrointestinal tract, which leads to nausea.
Accordingly, atropine is useful for treating nausea after high spinal
blockade

(25)

. Nausea and vomiting occur after spinal anesthesia

approximately 20% of the time, and risk factors include blocks higher
than T5, hypotension, opioid administration, and a history of motion
sickness(18).
There is no auto-regulation of hepatic blood flow, thus, hepatic
blood flow correlates to arterial blood flow

(26)

. So if mean arterial

pressure (MAP) is maintained after placing a spinal anesthetic, hepatic
blood flow will be maintained.
d) Urological Effects of Spinal Anesthesia:
Neuraxial blocks are a frequent cause of urinary retention, which
delays discharge of outpatients and necessitates bladder catheterization
in inpatients. However, some studies do not support this belief.(27)
Renal blood flow is auto-regulated. The kidneys remain perfused
when the MAP remains above 50mmHg. Transient decreases in renal
blood flow may occur when MAP is less than 50 mm Hg, but even after
long decreases in MAP, renal function returns to normal when blood

10

Review of literature

pressure returns to normal. In other words, renal perfusion changed very
little after spinal anesthesia(28).

III) Controversial contraindications:
Prior back surgery at the site of injection, inability to
communicate with patient or complicated surgery as in case of prolonged
operation, major blood loss or maneuvers that compromise respiration.

Technique of spinal anesthesia:
I) Spinal needles:
Spinal needles are commercially available in an array of sizes,
lengths, and bevel and tip designs (figure 3). All should have a tightly
fitting removable stylet that completely occludes the lumen to avoid
tracking epithelial cells into the subarachnoid space. Broadly, they can
be divided into either sharp-tipped or blunt-tipped needles.
The Quincke needle is a cutting needle with end injection. The
Whitacre and other pencil-point needles have rounded points and side
injection. The Sprotte is a side-injection needle with a long opening. It
has the advantage of more vigorous CSF flow compared with similar
gauge needles. However, this can lead to a failed block if the distal part
of the opening is in the subarachnoid (with free flow CSF), the proximal
part is not past the dura, and the full dose of medication is not
delivered(14).
The introduction of blunt-tipped (pencil-point) needles has
markedly decreased the incidence of postdural puncture headache. Also,
the one type of needles is provided in different sizes; in general the
smaller the gauge of the needle the lower the incidence of headache.

12

Review of literature

Figure 3: Spinal needles

(14)

II) Patient's Position (14):
a) Lateral Decubitus: Patient lies on his side with his knees flexed
and pulled high against the abdomen or chest, assuming a "fetal
position." An assistant can help the patient assume and hold this
position. (figure 4)

Figure 4: Lateral decubitus position

13

(14)

Review of literature

b) Sitting Position: The anatomic midline is often easier to
appreciate when the patient is sitting than when the patient is in the
lateral decubitus position especially if the patient is very obese. The
patient sits with his elbows resting on his thigh or a bedside table or he
can hug a pillow. Flexion of the spine (arching the back "like a mad cat")
maximizes the "target" area between adjacent spinous processes and
brings the spine closer to the skin surface. (figure 5)

Figure 5: Sitting position

(14)

c) Prone Position: This position may be used for anorectal
procedures utilizing a hypobaric anesthetic solution. The advantage is
that the block is done in the same position as the operative procedure
(jackknife) so that the patient does not have to be moved following the
block. The disadvantage is that CSF will not freely flow through the
needle, so that correct subarachnoid needle tip placement will need to be
confirmed by CSF aspiration. The prone position is also used whenever
fluoroscopic guidance is required.
14

Review of literature

III) Approaches:
a) Median Approach: The most common approach, the needle or
introducer is placed midline, perpendicular to spinous processes, aiming
slightly cephalad. When spinal needle goes through the dura mater, a
"pop" is often appreciated. Once this pop is felt the stylet should be
removed from the introducer to check for flow of CSF. When
performing a spinal anesthetic using the midline approach, the layers of
anatomy that are traversed (from posterior to anterior) are: Skin,
subcutaneous

fat, supraspinous

ligament, interspinous

ligament,

ligamentum flavum, dura mater, subdural space, arachnoid mater and
subarachnoid space (14).
b) Paramedian Approach: Indicated in patients who cannot
adequately flex because of pain or whose ligaments are ossified. The
injection site is located 1-1.5 cm lateral and caudal to the lower edge of
the spinous process. The puncture is carried out in a craniomedial
direction, at an angle of about 10-15 . When performing a spinal
anesthetic using the paramedian approach, the supraspinous and
interspinous ligaments are avoided, so that the ligamentum flavum is the
primary target on the way to the subarachnoid space (15).
c) Taylor or Lumbosacral Approach: This approach is useful in
patients with calcified or fusion of higher intervertebral spaces. This
approach is a paramedian injection via the intervertebral space of L5 and
S1, the largest interlaminar space in the spinal region. The injection site
is located about 1 cm medial and about 1 cm caudal to the posterior
superior iliac crest. The injection needle is advanced in a craniomedial
direction and at an angle of about 60d(15).

15

Review of literature

IV) Procedure (15):
1. Anatomic landmarks for the desired interspace of spinal
column are first identified. The iliac crests usually mark the
interspace between the L4-L5 vertebrae, and a line can be
drawn between them to help locate this interspace.
2. A sterile field is established with povidone-iodine applied with
three basic sponges, the solution is applied starting from the
injection site moving outward in a circular fashion.
3. A fenestrated drape is applied, and using sterile gauze, wipe
the iodine from the injection site to avoid initiation into the
subarachnoid space.
4. A skin wheal is raised with 2 ml of 1% lidocaine using a 25G
needle to the selected space.
5. A 17G introducer is passed through the skin wheal, angled
slightly cephalad through the epidermis, dermis, subcutaneous
tissue, supraspinous ligament, interspinous ligament, stopping
in the ligamentum flavum.
6. A small gauge spinal needle is inserted into the introducer,
passing through the epidural space, dura, and arachnoid to the
subarachnoid space stopping when the presence of CSF is
determined. The local anesthetic dose is slowly injected
7. The dose of the local anesthetic is injected according to the
level of the dermatome needed and the duration of surgery

Complications of spinal anesthesia:
I) Early complications:
a) Failed Anesthesia:
Spinal block is blind techniques that rely on indirect signs of
correct needle placement. It is associated with a small but significant
failure rate that is usually inversely proportional to the clinician's
experience. Failure may still occur even when CSF is obtained during
spinal anesthesia. Movement of the needle during injection, incomplete
entry of the needle opening into the subarachnoid space, subdural
injection, or loss of potency of the local anesthetic solution may be
responsible (14).
b) Intravascular Injection:
Inadvertent intravascular injection of the local anesthetic can
produce very high serum levels leading to systemic toxicity. this
complication is seen primarily with epidural and caudal blocks because
the dosage of medication for spinal anesthesia is relatively small (14).
c) High or total spinal anesthesia:
High or Total spinal anesthesia occurs when local anesthetic
spreads high enough to block the most or the entire spinal cord and
occasionally

the

brainstem during

spinal

anesthesia.

Profound

hypotension and bradycardia are common secondary to complete
sympathetic blockade. Respiratory arrest may occur as a result of
respiratory muscle paralysis or dysfunction of brainstem respiratory
control centers(30).

18

Review of literature

d) Severe hemodynamic changes:
Some cases of sudden cardiac arrest in healthy patients receiving
spinal anesthesia were identified.(22) Because these cases seemed to
appear suddenly after stable hemodynamic status, it was concluded that a
poorly understood potential exists for sudden cardiac arrest in healthy
patients. Also cases of severe bradycardia after spinal anesthesia had
been recognized for many years.(31, 32)
e) Shivering: Will be discussed later in details.

II) Late complications:
a) Postdural puncture headache (PDPH):
This PDPH is not exclusively related to spinal anesthesia; it also
occurs after myelography and diagnostic lumbar puncture. PDPH is
believed to result from leakage of CSF from a dural defect and decreased
intracranial pressure. Loss of CSF at a rate faster than it can be produced
causes traction on structures supporting the brain, particularly the dura
and tentorium. Increased traction on blood vessels also likely contributes
to the pain. Traction on the cranial nerves may occasionally cause
diplopia (usually the sixth cranial nerve) and tinnitus

(14)

. Definitive

treatment is Epidural blood patching therapy; its safety and efficacy have
been well documented, and contemporary practice has validated that
epidural blood patch continues to have a greater than 90% improvement
rate.(33)
Factors increasing the incidence of post-spinal puncture headache
or unrelated to its development are listed in table 3 and table 4:

19

Review of literature

(34)

Table 3:Factors That May Increase the Incidence of PDPH
Age

Younger more frequent

Gender

Females more than males

Needle size

Larger more than smaller

Needle bevel

- Less when the needle bevel is placed in the long axis of the neuraxis
- Non-cutting needle tip designs have a lower frequency of PDPH than
cutting needle tip designs do.

Pregnancy

More when pregnant

Dural
punctures
number

More with multiple punctures

(34)

Table 4:Factors Not Increasing the Incidence of PDPH
Continuous spinals
Timing of
ambulation

An arbitrary period of recumbency after spinal anesthesia has not been
found to decrease the incidence of PDPH, and some data indicate that
early ambulation may actually decrease its incidence.

b) Backache:
As a needle passes through skin, subcutaneous tissues, muscle,
and ligaments it causes varying degrees of tissue trauma (14). A localized
inflammatory response with or without reflex muscle spasm may be
responsible for postoperative backache. Data from Brown and Elman(35)
demonstrate that approximately 25% of all surgical patients undergoing
anesthesia, regardless of anesthetic technique, experience backache.
Backache after neuraxial block should not immediately be attributed to
k
VN
N
MT
R
VP
lWO NKJ
L
S(14).

20

Review of literature

c) Spinal hematoma:
Needle or catheter trauma to epidural veins often causes minor
bleeding in the spinal canal although this is usually benign and selflimiting. A clinically significant Spinal hematoma is a rare but
potentially devastating complication of spinal and epidural anesthesia,.
Patients most commonly present with numbness or lower extremity
weakness. Early detection is critical because a delay of more than 8
hours in decompressing the spine reduces the odds of good recovery. It
can occur following spinal or epidural anesthesia, particularly in the
presence of abnormal coagulation or bleeding disorder. A mass effect
causes direct pressure injury and ischemia to the spinal cord and
nerves(14).
d) Neurologic injury after spinal anesthesia:
Serious neurologic injury is a rare but widely feared complication
of spinal anesthesia. Multiple large studies of spinal and epidural
anesthesia report that neurologic injury occurs in approximately 0.03 to
0.1% of all central neuraxial blocks, although in most of these studies the
block was not clearly proven to be causative

(36)

. Persistent paresthesias

and limited motor weakness are the most common injuries, although
paraplegia and diffuse injury to cauda equina roots (cauda equina
syndrome) do occur rarely. Injury may result from direct needle trauma
to the spinal cord or spinal nerves, from spinal cord ischemia, from
accidental injection of neurotoxic drugs or chemicals, from introduction
of bacteria into the subarachnoid or epidural space, or very rarely from
epidural hematoma

(36)

. It should be noted that not all neurological

deficits occurring after a regional anesthetic are the result of the block(14).

21

Review of literature

e) Transient Neurological Symptoms (TNS):
TNS are characterized by back pain radiating to the legs without
sensory or motor deficits, occurring after the resolution of spinal block
and resolving spontaneously within several days. It is most commonly
associated with hyperbaric lidocaine, but has also been reported with
other anesthetics like bupivacaine

(37)

. The pathogenesis of TNS is

believed to represent concentration-dependent neurotoxicity of local
anesthetics (14).
f) Urine retention:
Local anesthetic block of S2i
S4 root fibers decreases urinary
bladder tone and inhibits the voiding reflex. These effects are most
pronounced in male patients. Urinary bladder catheterization should be
used for all but the shortest acting blocks. If a catheter is not present
postoperatively, close observation for voiding is necessary. Persistent
bladder dysfunction can also be a manifestation of serious neural injury
occurred (14).
g) Infection:
Infection of the subarachnoid space can follow neuraxial blocks as
the result of contamination of the equipment or injected solutions, or as a
result of organisms tracked in from the skin. Indwelling catheters may
become colonized with organisms that then track deep, causing infection.
Fortunately, these are rare occurrences (14).

heat production up to 600% after general or regional anesthesia(2).
Regional anesthesia is associated with post-anesthetic shivering in up to
60% of patients (3).

Consequences:
Although shivering may have beneficial thermoregulatory effects
it may causes major discomfort to patients and aggravate wound pain by
stretching incisions(6)

and increase intracranial(7) and intraocular

pressure.(8)
Also it may increase tissue oxygen demand by as much as 500%
and accompanied by increases in minute ventilation and cardiac output
to maintain aerobic metabolism. This may be deleterious in patients with
impaired cardiovascular reserve or a limited respiratory capacity.(9)
Shivering also may interfere with the monitoring of patients by
causing artifacts of the ECG, blood pressure, and pulse oximetry
recording.(10)

Grading:
Grading of shivering is important to allow meaningful
comparisons of interventions in this area. In this study the presence of
shivering is observed and graded by using a scale similar to that
validated by Tsai and Chu(38) where:

23

Review of literature

0 = No shivering.
1 = Piloerection or peripheral vasoconstriction but no visible
shivering.
2 = Muscular activity in only one muscle group.
3 = Muscular activity in more than one muscle group but not
generalized.
4 = Shivering all over the body.

Pathophysiology
The etiology of shivering still remains poorly understood. The
obvious etiology is said to be normal thermoregulatory mechanism in
response to core hypothermia (4).
The way in which core hypothermia occurs in the post-anesthesia
period is known and consistent with a combination of competitive
inhibition of thermoregulatory responses by the anesthetics, with a
decrease in metabolism, and exposure to a cold environment.(39)
Schematically, the drop in core temperature during general
anesthesia occurs in three phases (figure 6):
1. Phase I (Redistribution): is immediately after anesthesia
induction and consists in an internal transfer of core heat to
the periphery, known as internal redistribution. The
temperature decrease takes place without heat loss.
2. Phase II (Heat loss): is a drop in core temperature as a
result of heat losses (via the cutaneous route, by the
exposure of viscera or by the perfusion of cold solutions)
being higher than heat gains.
24

Review of literature

3. Phase III (Equilibrium): after a decrease in body
temperature that varies depending on the anesthetic
products

and

concentrations

used,

cutaneous

vasoconstriction occurs. During this period, the core
temperature is almost stable.

(40)

Figure 6: Unintentional hypothermia during general anesthesia

At recovery and the waning of the effect of the anesthetic drugs,
thermoregulation is no longer inhibited and other physiological
responses to cold such as shivering appear. Therefore, prevention of
post-anesthesia hypothermia will automatically reduce the incidence of
post-anesthesia shivering. (40)
However

non

thermoregulatory

shivering

may

occur

in

normothermic patients. The mechanism is unknown but may be related
to the postoperative pain, direct effect of certain anesthetics, hypoxia
hypercapnia or respiratory alkalosis, the existence of pyogens, early
recovery of spinal reflex activity, sympathetic overactivity and/or
adrenal suppression (5).

25

Review of literature

Thermoregulation:
Similar

to

other

physiological

systems,

the

thermoregulatory system is often divided into 3 components

(41)

human
:

1. Thermo receptors and afferent neural pathways.
2. A center for integration of this input.
3. Effector pathways.
A simplified schematic representation of the shivering pathway is
illustrated in figure 7

Figure 7: Schematic diagram of the shivering pathway

26

(41)

Review of literature

1. Afferent input:
Afferent thermal input is generated by peripheral (skin & mucous
membranes) and visceral thermoreceptors (deep abdominal and thoracic
tissues in addition to spinal cord, hypothalamus and other brain tissues).
Cold thermoreceptors are anatomically and physiologically distinct from
those of warmth. Cold signals are transmitted via A nerve fibers while
warmth signals via unmyelinated C fibers, although there is some
overlap(41).The mean skin temperature represents 20% of the total
thermoregulatory input.(11)
2. The center for integration of the afferent input:
That afferent thermal input is projected by the lateral
spinothalamic tract to the hypothalamic thermoregulatory centers and to
nuclei within the reticular formation in the pons. This input is modulated
by spinal cord and brain stem especially the nucleus raphe magnus which
facilitates transmission of thermal information to the hypothalamus and
has an inhibitory role in shivering and the locus subcoeruleus which has
a predominantly excitatory role in shivering. The preoptic area of the
anterior hypothalamus appears to be the central integrator that compares
the integrated afferent thermal inputs with the threshold temperatures for
each thermoregulatory response(41).
3. Efferent responses:
The efferent shivering pathway starts at an area between the
anterior and posterior hypothalamus and makes multiple connections
within the reticular formation before it ends at the motor neurons.

27

Review of literature

A reference temperature (set point), most probably generated by a
network of thermal insensitive neurons in the pre-optic area is compared
with feedback from the skin and core thermoreceptors. An error signal,
proportional to the difference between the set point and feedback signal,
is generated which activates thermoeffector pathways that control heat
production and heat loss(41).
In humans, core temperature is normally maintained within a tight
J
V
PN

)
d
4i

)d
4 S
VW V J

Nk
R
VN N W
T
M J
V
PN
lW

k N WVN J
Tb
W
VNl4WN N NJ N J
KWNW K
N
T
W

R J
VP
N

trigger thermoregulatory responses such as vasoconstriction and
shivering with lower and vasodilatation and sweating with higher core
temperatures. The core temperature triggering each thermoregulatory
response is known as the threshold (i.e. each thermoregulatory response
has its threshold). How the body determines these thresholds is unknown
but the mechanism appears to be mediated by norepinephrine,
acetylcholine, dopamine, 5-hydroxytryptamine (5-HT), prostaglandin E,
and neuropeptides.(11)
The normal response to hypothermia involves thermoregulatory
vasoconstriction to decrease cutaneous heat loss, and maintain heat
within the core. Maximal vasoconstriction usually occurs before
thermoregulatory shivering occurs. When the core temperature decreases
to a certain point, known as the shivering threshold, thermoregulatory
shivering then occurs. The threshold temperature at which shivering
occurs may be lower in males relative to females(42), and may also
decrease with age.(43) Also, it can be altered by many factors like
exercise, food intake, infection, thyroid dysfunction, and drugs
(including anesthetics, alcohol, sedatives, and nicotine) (41).
28

Review of literature

Thermoregulation and Neuraxial anesthesia:
Core temperature during neuraxial anesthesia decreases in the
same pattern as in during general anesthesia. During the first hour of
neuraxial anesthesia core hypothermia results from redistribution of core
body heat to the peripheral tissues (phase I). Then it continue to decrease
as a result of the accompanying thermoregulatory impairment that allows
continued heat loss (phase II). This impairment appears to be due to an
altered perception of temperature in the blocked dermatomes by the
hypothalamus as opposed to a central drug effect as seen with general
anesthetics. But vasoconstriction is impaired below the level of the block
which results in more cutaneous heat loss, the heat content of limbs
continues to fall aggravating the hypothermia (phase III). (44)
Thus Thermoregulation is impaired during neuraxial anesthesia
and the result typically is core hypothermia which usually is not
perceived by the patient resulting in a frequent clinical paradox, a
shivering patient who denies feeling cold (41).
For the first 30 minutes of anesthesia, core temperature decreased
significantly faster in patients given spinal block when compared with
those given epidural block. After 30 minutes, core temperatures
decreased at identical rates during epidural and spinal anesthesia, with
the end

result

being

lower

core temperature in

the

spinal

group(45).Though the intensity of shivering with epidural anesthesia may
be higher than that with spinal anesthesia. This may be due to the greater
intensity of the motor block with spinal block compared with that in
epidural block, such that patients are actually unable to shiver during
spinal block. Also it has long been known that the spinal cord has
29

Review of literature

thermoreceptors and is involved in thermoregulation. Administration of
cold fluids into the epidural space may result in cooling of large epidural
veins, which in turn communicate with the basal sinuses. This might also
provide an explanation for the difference in shivering intensity for
epidural and spinal anesthesia(41).
A decrease in core temperature (measured at the tympanic
N KJ
VN W
O )d
4R O
O
R
L
R
N
V WR
V
ML
N RNR
VPR
VV
WV-pregnant
volunteers undergoing epidural anesthesia(46).

Prevention and Management
I) Non-pharmacological measures
As core hypothermia is responsible for post-anesthetic shivering in
most patients, prevention of its occurrence decreases the incidence of
shivering. Core hypothermia prevention during anesthesia entails
limiting the effects of internal redistribution (Phase I), and reducing and
making up for the heat losses (Phase II).
i.

Preoperative skin surface rewarming efficiently limits the
effects of internal redistribution. Covering the patient with
forced-air warmer systems for 30 minutes before the induction
of anesthesia is enough to eliminate the phenomenon of
internal redistribution(47). If shivering already occurred they can
reduce the frequency of the shivering and was found in all
patients to reduce the duration (48).

ii.

Another method entails increasing the heat content of the
patient by generating endogenous production. Providing the
patient amino-acid solution resulted in values close to
normothermia after hysterectomy(49).
30

Review of literature

iii.

Covering the patient as much as possible with the surgical
drapes, which are excellent insulators, is sufficient to
significantly reduce the loss of heat from the skin(50).

iv.

As patients mainly lose calories through radiation and
convection on the skin surface, it also helps to raise the
WNJR
VP WW

N NJ N 1&d
4

J
MR
J
V N
J aN

applied in the recovery and operating rooms are efficient ways
of preventing post-anesthetic shivering or rapidly inhibiting it
when it occurs. This method is especially useful when the
patient is uncovered (i.e. at the beginning and end of the
operation). Also when the surgical field is very large or if a
large amount of viscera is exposed, room temperature remains
an important factor to limit heat loss. (50)
v.

When a perfusion of a large volume of fluids or cold blood
products are needed, intravenous solution rewarming prevents
the patient from cooling down. (50)

II) Pharmacological measures:
Multiple pharmacologic strategies to combat shivering have been
evaluated. A majority of these have been applied in the peri-operative
setting due to the potentially deleterious effects of hypothermia and
shivering in postoperative recovery
a) Opioids:
Numerous peptides participate in central thermoregulatory control.
Opioid peptides can also affect changes in body temperature. Possible
sites of action include the preoptic anterior hypothalamus, dorsal raphe
nucleus, raphe magnus and the spinal cord(11).
31

Review of literature

1. Meperidine is unique among opioids due to its special
antishivering effect

stimulate norepinephrine and acetylcholine release. Depressor effects of
these neurotransmitters at the dorsal horn may modulate the cutaneous
thermal input (11).
1. Clonidine

was found effective in preventing shivering

when compared with Meperidine(53)
2. Similar

to

clonidine,

premedication

with

IM

dexmedetomidine reduces the incidence of postoperative
shivering compared with midazolam(54).

32

Review of literature

c) 5-HT uptake inhibitors
5-HT impacts thermoregulatory responses through its action on
different sites in the hypothalamus, midbrain and medulla. It is likely
that the balance between the modulatory 5-HT and norepinephrine inputs
is important for short and long term thermoregulatory control of the
shivering threshold (11).
1. Tramadol is a centrally acting analgesic with multiple
potential mechanisms by which it affects thermoregulation.
Several randomized studies have indicated that tramadol is
effective for prevention (7) and treatment of shivering (5).
2. Nefopam, is a potent inhibitor of 5-HT uptake with an
analgesic with anti-shivering properties (55).
d) 5-HT agonists/antagonists:
1. Buspirone, a 5-HT1A partial agonist, acts synergistically
with meperidine and it has been used as such in several
protocols of induced hypothermia(56).
2. Ondansetron, one of 5-HT3 antagonists, has a potential
antishivering effect(57).
e) N-Methyl-d-Aspartate (NMDA) antagonists:
NMDA receptors modulate noradrenergic and serotonergic
neurons in the brain stem although these and other potential mechanisms
in thermoregulation remain unproven.

33

Review of literature

1. Magnesium sulfate is a competitive NMDA receptor
antagonist which has been shown effective in postanesthetic shivering control(58).
2. Ketamine, another competitive NMDA receptor antagonist
has been shown effective in preventing (12) and inhibiting (13)
post-anesthetic shivering.
f) Others
Many other individual pharmaceutical agents have been found
having properties like Physostigmine a nonselective, centrally acting
cholinesterase

inhibitor

(53)

,the

analeptic

Dexamethasone (60)

34

Doxapram

(59)

and

Review of literature

Local anesthetics
Local anesthetics are compounds with the ability to interrupt the
transmission of the action potential in excitable membranes. They bind
to specific receptors in the Na+ channels and their action at clinically
recommended doses is reversible.

Chemical structure of local anesthetics:
A typical local anesthetic is composed of two moieties, one a
benzene ring (lipid soluble, hydrophobic) and the other an ionizable
amine group (water soluble, hydrophilic), linked by a chemical chain.
This chemical chain can be either of the ester or amide types defining
two different groups of local anesthetics, aminoester or aminoamide
compounds (61).

duration of action of local anesthetics by facilitating their transfer
through membranes and binding the drug close to the site of action and
thereby decreasing the rate of metabolism by plasma esterase and liver
enzymes(62).
II) Protein binding:
Local anesthetics are bound in large part to plasma and tissue
proteins. The bound portion is not pharmacologically active. The most
35

Review of literature

R WJ
V KR
VM
R
VP

WN
R
V R
V T
J J JN J
T
K R
V J
V
M p1-acid

glycoprotein (AAG). Although albumin has a greater binding capacity
than AAG, the latter has a greater affinity for drugs with pKa higher than
8 like most local anesthetics. However changes in protein binding are
only clinically important for drugs highly protein bound such as
bupivacaine, which is 96%, bound

(63)

. The fraction of drug bound to

protein in plasma correlates with the duration of action of local
anesthetics: the greater the protein binding, the longer the duration of
action (bupivacaine = ropivacaine > tetracaine > mepivacaine >
lidocaine > procaine) (61).
III) pKa:
By definition the pKa is the pH at which 50% of the drug is
ionized and 50% is present as a base. It determines the ratio between the
ionized (cationic) and the uncharged (base) forms of the drug. The pKa
generally correlates with the speed of onset of most local anesthetics.
The closer the pKa is to the physiologic pH the faster the onset (e.g.,
lidocaine with a pKa of 7.7 is 25% non-ionized at pH 7.4 and has a more
rapid onset of action than bupivacaine with a pKa of 8.1 which is only
15% nonionized). Increasing the pH of the drug solution will increase
the fraction of the nonionized form, resulting in a faster onset. Most local
anesthetic solutions are prepared commercially as a water-soluble HCL
salt (pH 6 -7) (62).

Mechanism of local anesthetic action:
Local anesthetics produce conduction blockade of neural impulses
by preventing the passage of sodium ions through ion selective sodium
channels in nerve membrane. It is likely that local anesthetics stabilize
36

Review of literature

and maintain sodium channels in the inactivated closed state by binding
to specific receptors located in the inner portion of sodium channels.
Local anesthetics may prevent the change in sodium permeability by
obstructing sodium channels near their external openings. Failure of
permeability to sodium ions slows the rate of depolarization so the
threshold potential is not reached and an action potential is not
propagated along the nerve membrane. The ion gradient and resting
membrane potential are unchanged(62).

Pharmacokinetics:
Systemic absorption:
It depends on blood flow, which is determined by the following
factors:
1. The vascularity at the Site of Injection: The rate of systemic
absorption is proportionate to the vascularity of the site of
injection: intravenous > tracheal > intercostal > caudal >
paracervical

> epidural

> brachial plexus > sciatic >

subcutaneous(61).
2. Dose of the anesthetic agent: For a given site of injection, the rate
of systemic absorption and the peak plasma level are directly
proportional to the dose of local anesthetic deposited(61).
3. The type of the anesthetic agent: The rate of systemic absorption
differs with individual local anesthetics. In general, more potent,
lipid-soluble agents are associated with a slower rate of absorption
than less lipid-soluble compounds. Sequestration into lipid-rich
compartments may not be the only explanation. Local anesthetics
exert direct effects on vascular smooth muscles in a concentration37

Review of literature

dependent manner. At low concentrations, more potent agents
appear to cause more vasoconstriction than less potent agents,
thereby decreasing the rate of vascular absorption. At high
concentrations, vasodilator effects seem to predominate for most
local anesthetics (61).
4. Presence of Vasoconstrictors: The addition of epinephrine or
less commonly phenylephrine causes vasoconstriction at the site
of administration. The consequent decreased absorption increases
neuronal uptake, enhances the quality of analgesia, prolongs the
duration of action, and limits toxic side effects. The effects of
vasoconstrictors are more pronounced with shorter-acting
agents(62).
Distribution:
Distribution depends on organ uptake, which is determined
by the following factors:
1. Tissue Perfusion: The systemic distribution of local anesthetics
can be described sufficiently by a two-compartment model. The
highly perfused organs (brain, lung, liver, kidney, and heart) are
responsible for the initiJ
T JR
M

Metabolism and Excretion:
Esters: Ester local anesthetics are predominantly metabolized by
pseudocholinesterase. Ester hydrolysis is very rapid, and the watersoluble metabolites are excreted in the urine. Procaine and benzocaine
are metabolized to P-aminobenzoic acid (PABA), which has been
associated with allergic reactions. Patients with genetically abnormal
pseudocholinesterase are at increased risk for toxic side effects, as
metabolism is slower. Cerebrospinal fluid lacks esterase enzymes, so the
termination of action of intrathecally injected ester local anesthetics, eg,
tetracaine, depends on their absorption into the bloodstream. In contrast
to other ester anesthetics, cocaine is partially metabolized (Nmethylation and ester hydrolysis) in the liver and partially excreted
unchanged in the urine (62).
Amides: Amide local anesthetics are metabolized (N-dealkylation
and hydroxylation) by microsomal P-450 enzymes in the liver. The rate
of

amide

metabolism

depends

on

the

specific

agent

(prilocaine > lidocaine > mepivacaine > ropivacaine > bupivacaine), but
overall is much slower than ester hydrolysis. Decreases in hepatic
function (eg, cirrhosis of the liver) or liver blood flow (eg, congestive
heart failure, vasopressors, or H2-receptor blockers) will reduce the
metabolic rate and predispose patients to systemic toxicity. Very little
drug is excreted unchanged by the kidneys, although the metabolites are
dependent on renal clearance (62).

39

Review of literature

Bupivacaine

Figure 8: Chemical structure of bupivacaine

(61)

Physiochemical characteristics:
Bupivacaine is an amide long acting local anesthetic agent that is
chemically related to mepivacaine and differs only in having a butyl side
chain in place of a methyl group. Both drugs have potency and toxicity
approximately four times greater than those of lignocaine

Pharmacokinetics
The systemic absorption of bupivacaine as a local anesthetics is
determined by: the site of injection, dosage, addition of a vasoconstrictor
agent, and the pharmacologic profile of the agent itself (61).
The systemic distribution of bupivacaine can be described
sufficiently by a two-compartment model. The rapid disappearance
JN p

JN R KN
T
R
NN
M W KN N
T
JN
M W ptake by rapidly

40

Review of literature

equilibrating tissues (i.e., tissues that have high vascular perfusion).
Then a T
WN

JNr JNWOM
RJ N
JJ
VL
NOW KT
W
W
M(64).

The physicochemical properties which influence anesthetic
activity are lipid solubility, pKa and protein binding. Lipid solubility
appears to be the primary determinant of intrinsic anesthetic potency.
The duration of anesthesia is primary related to the degree of protein
binding of the various local anesthetics. Physiologic or pathologic
conditions that alter either protein content or protein structure will
influence the amount of free local anesthetic.
Bupivacaine is the first local anesthetics that combine the
properties of an acceptable onset (20-30 min), profound conduction
blockade, significant separation of sensory anesthesia and motor
blockade and long duration of action (the average duration of surgical
analgesia varies 90 to 200 minutes when used for spinal anesthesia) (61).
Bupivacaine like other local anesthetics with an amide structure is
detoxified in the liver by conjugation with glucuronic acid. Most of the
drug is metabolized partly by N-dealkylation. Decreased hepatic function
will reduce the metabolic rate and lead to systemic toxicity (61).
About 10% of the drug is excreted unchanged by the kidney. A
glucuronide conjugate is also excreted(61)

Mechanism of action(62):
Bupivacaine (like other local anesthetics) produces conduction
blockade of neural impulses by preventing the passage of sodium ions

41

Review of literature

Pharmacodynamics
I) Local anesthetic action:
Bupivacaine is used in a concentration of 0.125%, 0.25%, 0.5%
and 0.75% for various regional anesthetic procedures including
infiltration, peripheral nerve block, extradural and spinal anesthesia. It is
widely used as a spinal anesthetic, either as a hyperbaric solution with
8.25% dextrose or by using the nearly isobaric 0.5% solution.
Bupivacaine bolus doses at a concentration of 0.125% produce
adequate analgesia in many clinical settings with only mild motor
deficits(67). Continuous epidural infusions of Bupivacaine as dilute as
0.0625% to 0.1% are useful for labor epidural analgesia, especially when
administered in combination with opioids and other additives.
Bupivacaine 0.25% may be used for more intense analgesia (particularly
during combined epidural) with moderate degrees of motor block.
Bupivacaine at concentrations of 0.5% to 0.75% is associated
with a more profound degree of motor block, which makes these
solutions most suitable for major surgical procedures, particularly when
epidural anesthesia is not combined with general anesthesia(61).
II) Central nervous system:
Bupivacaine has a central excitatory effects (restlessness,
agitation, nervousness and paranoia) followed by depression (slurred
speech, drowsiness and unconsciousness) (61).

Dosage:
For spinal anesthesia, a concentration of 0.5% is usually used. The
dose for perineal and lower limb surgery is 4-6 mg, while for lower
abdominal surgery is 8-10 mg and for blockade up to T4 level, it is 12-20
mg (table 2). For epidural blockade a dose of 1-2 ml of 0.25-0.5% for
each spinal segment to be anaesthetized is given. The maximum dose is
3mg/Kg(68).

Adverse effects: (toxicity):
Toxic effects of local anesthetics are dose related and dependent
on systemic absorption which is related to the amount of the drug used,
the rate of injection, the vascularity of the area injected, any vasoactive
properties of the drug, the toxicity of the drug and its rate of deactivation
and excretion(68).

43

Review of literature

I) Cardio vascular system (CVS) toxicity:
Fall of the blood pressure is usually the first sign of a systemic
affection of CVS(68). Cardiodepression, Ventricular arrhythmias, Cardiac
arrest and death may occur with local Anesthetics toxicity (Bupivacaine
in particular)(69, 70).
II) Central nervous system (CNS) toxicity:
Initial symptoms such as visual or hearing disturbances, numbness
of the tongue and mouth, dizziness, tingling and parasthesia are seen.
Dysarthria, muscular rigidity and muscular twitching are more serious
and may precede the onset of grand mal convulsions that may last from
seconds to several minutes. Coma may follow (71).

44

Review of literature

Midazolam

Figure 9: Chemical structure of midazolam

(61)

Physiochemical properties:
Midazolam is a benzodiazepine derivative having imidazole ring
fused in positions 1, 2 with a diazepam ring. This imidazole ring
accounts for the basicity, stability and rapid metabolism of the
midazolam aqueous solution. When the environmental pH falls below 4,
the imidazole ring opens between the 4 and 5 positions producing a polar
water soluble primary amine derivative. At physiological pH, the drug is
present in the closed ring form and lipid solubility is increased

(72)

. The

high lipophilicity has a number of clinical consequences including rapid
absorption of midazolam from the gastrointestinal tract and rapid entry
into brain tissue after IV administration
midazolam is 362 while its pKa is 6.15
96% (75).

45

(73)

(74)

. The molecular weight of

and its protein binding is 94-

Review of literature

Pharmacokinetics
Midazolam is absorbed very rapidly from the gastrointestinal tract
after oral administration

(76)

. Midazolam undergoes extensive hepatic

first phase metabolism resulting in a systemic availability of
approximately 40-50% of the orally administered dose in its non
metabolized forms. Therefore, the oral dose of midazolam must be
approximately twice as high as intravenous dose to achieve comparable
clinical effect

(73)

. After intramuscular injection, midazolam is 80% to

100% absorbed. A physiological pH maintains the closed ring and
enhances the lipid solubility of midazolam which contributes to the
speed of onset of activity after intravenous administration

(77)

.

Midazolam is rapidly absorbed by the rectal route via the superior
hemorrhoidal veins that lead to the portal circulation so the drug
undergoes

first

administration

(78)

phase

hepatic

extraction

following

rectal

.

Although Midazolam is water, soluble at low pH, its imidazole
ring closes at physiological PH, causing an increase in its lipid solubility
which leads to rapid entry of midazolam into brain tissue after
intravenous administration and redistribution is fairly rapid

(79)

.

Midazolam is extensively bound to plasma proteins (94-96%) with only
about 4% being unbound(80). Albumin appears to be the major sources of
binding, decrease in plasma protein concentration or reduction in the
extent of binding, increase the fraction of free drug (81).
Midazolam is hydroxylated by hepatic microsomal oxidative
mechanisms. The resultant metabolites (mainly l-hydroxy-midazolam)

46

Review of literature

are excreted in urine in the form of glucuronide conjugates. Very little
amount of the drug excreted unchanged in urine (79).

Mechanism of action
Midazolam has a relatively high affinity for the benzodiazepine
receptor, approximately two times that of diazepam(82). It reduces s
amino-butyric acid (GABA) reuptake from synaptic clefts, thereby
causing accumulation of GABA with increased stimulation of the GABA
receptors thus inducing a conformational changes which triggers the
opening of the chloride channels (83). The opening of the channel and the
concomitant influx of chloride ions into the postsynaptic cell
hyperpolarize its cell membrane delaying the propagation of the action
potential and potentiate the synaptic inhibition

(84)

. That explains why

there was a reduction in the repetitive firing in response to depolarizing
pulses in spinal cord neurons (85).

Pharmacodynamics:
I) Central nervous system (CNS) effects:
Clinically, Midazolam is 3 to 4 times as potent as diazepam
because of its increased affinity for the benzodiazepine receptor (86). The
maximum clinical effect of Midazolam is reached in about 3 minutes
after IV injection

hypoxia and can be useful for patients who have increased intracranial
pressure(91).
II) Cardiovascular effects:
Midazolam produces minimal haemodynamic changes including
small reduction in the blood pressure and small increase in the heart
rate(89). However, marked decrease in blood pressure can be observed in
hypovolaemic patients
(92)

activity

because midazolam depresses baroreflex

which is increased to compensate for this hypovolaemia. This

effect is especially important in the elderly and in those who have
extensive major sympathetic blockade during regional anesthesia(93).
III) Respiratory effects:
In healthy humans IV Midazolam produces a 32-40% decrease in
the tidal volume associated with an increase in the respiratory rate so the
minute volume remains constant.Midazolam neither reduces the
functional residual capacity nor residual lung volume and it does not
cause bronchoconstriction(94).
IV) Other:
Midazolam significantly decreases intraocular pressure (IOP)
within 3 minutes of its injection. The mechanism by which Midazolam
decreases IOP involves a relaxation of the extraocular muscles, a
moderate reduction in arterial blood pressure and an increase in the
outflow of aqueous humor(95). Midazolam reduces the autonomic and
hormonal responses to emotional or surgical stresses. Catecholamines
levels are reduced after Midazolam treatment (96).

48

Review of literature

Adverse reactions:
Midazolam can cause respiratory
depression

(98)

, ventricular irritability

(99)

(97)

, and cardiovascular

and a change in the baroreflex

control of heart rate. Respiratory obstruction may occur if deep sedation
occurs

(97)

. In addition, cardio-respiratory depression and death have

been reported (99).
After Midazolam induction, the incidence of nausea and vomiting
ranges from none to 15% (100).
Although midazolam has a short half-life; it influences
psychomotor function for several hours after its administration. Thus,
patients should not drive or operate machinery for 8 hrs after receiving
the drug

(101)

. A paradoxical reaction is a serious side effect of all

benzodiazepines, including midazolam, although it is rare and as yet not
fully understood. The subjects become confused and aggressive and can
harm themselves. Flumazenil 0.1 mg/Kg is very effective in treating and
calming these patients (102).
Other uncommon postoperative side effects following midazolam
administration include dizziness, diplopia, hiccough and bad taste (79).

Clinical uses and dosage:
I) Premedication:
It is generally safe to premedicate with a Midazolam dose of 0.05
mg/kg IV with a maximal dose of 2.5 mg. In elderly patients, the initial
dose should be no higher than 1-1.5 mg

49

(103)

. In children, midazolam is

Review of literature

an effective oral premedication. No marked side effects have been
observed after doses of 0.4 - 0.5mg/kg (104).
II) Intravenous sedation:
Midazolam is a useful IV adjuvant to local or regional anesthesia
for a variety of therapeutic and diagnostic procedures. The short-term
anterograde amnesia allows endoscopy or injection of a local anesthetic
without recall (105). Midazolam, in an initial IV dose of 0.08 mg/Kg with
incremental doses of 0.04 mg/kg at 3 minutes interval until the desired
effect has been reached, produces excellent sedation in patients receiving
regional anesthesia and provides a much greater degree of amnesia than
diazepam (106).
III) Induction of anesthesia:
As an induction agent, Midazolam produces sleep and amnesia but
it does not have a great analgesic effect

(73)

. The induction dose of

Midazolam ranges from 0.1-0.4 mg/Kg (89).
Midazolam is less commonly used as an induction agent for
outpatients because of concerns regarding delayed recovery and residual
amnesia

Physiochemical properties of ketamine:
Ketamine hydrochloride is a non-barbiturate
non barbiturate anesthetic that
belongs to the phencyclidine group of drugs.
Ketamine has a molecular weight of 238, is partially water
soluble, and forms a white crystalline salt with a pKa of 7.5

(109)

. It has

lipid solubility 5 to 10 times that of thiopental (110).
It is formulated as a slightly acid (pH 3.5 to 5.5) sterile solution
for intravenous or intramuscular injection in concentrations of 10
10-, 50-,
and 100-mg
mg ketamine base per milliliter. Ketamine consists of two
stereoisomers, S(+) and R(-).
R( The S(+) is moree potent and is associated
with fewer psychomimetic effects (111).

Pharmacokinetics of ketamine:
Ketamine is administered intravenously or intramuscularly.

51

Review of literature

The anesthetic action is terminated by a combination of
redistribution from the CNS to slower equilibrating peripheral tissues
and by hepatic metabolism.
Ketamine has a low degree of protein binding (12%). Because
ketamine has a low molecular weight, a pKa near the physiologic pH, and
relatively high lipid solubility, it crosses the blood-brain barrier rapidly
and has an onset of action within 30 to 60 seconds of administration. The
maximal effect occurs in about 1 minute.
The duration of ketamine anesthesia after a single IV
administration of a general anesthetic dose (2 mg/kg) is 10 to 15
minutes. The ketamine plasma concentration has an initial slope lasting
about 45 minutes with a half-life of 10 to 15 minutes where full
orientation to person, place, and time occurs. This slope corresponds
clinically to the anesthetic effect of the drug (figure 11). (111)

Figure 11: Simulated time course of plasma levels of ketamine after
an induction dose of 2 mg/kg (111)

52

Review of literature

Ketamine is metabolized by hepatic microsomal enzymes. The
major pathway involves N-demethylation to form norketamine
(metabolite I), which is then hydroxylated to hydroxynorketamine. These
products are conjugated to water-soluble glucuronide derivatives and are
excreted in the urine (109).
Norketamine has 20% to 30% of the activity of the parent
compound and may contribute in prolonging the analgesia provided by
either a bolus or infusion of ketamine (112).

Mechanism of action of ketamine:
Ketamine has been demonstrated to be an N-Methyl-D-Aspartate
(NMDA) receptor antagonist. Ketamine has multiple effects throughout
the central nervous system, including blocking polysynaptic reflexes in
the spinal cord and inhibiting excitatory neurotransmitter effects in
selected areas of the brain. In contrast to the depression of the reticular
activating system induced by the barbiturates, ketamine functionally
"dissociates" the thalamus which relays sensory impulses from the
reticular activating system to the cerebral cortex, from the limbic cortex
which is involved with the awareness of sensation (dissociative
amnesia). Although some brain neurons are inhibited, others are
topically

Pharmacodynamics of ketamine:
I) Central nervous system effects:
Ketamine produces dose-related unconsciousness and analgesia.
Patients anesthetized with ketamine have profound analgesia, but keep
their eyes open and maintain many reflexes (dissociative anesthesia).
Corneal, cough, and swallow reflexes all may be present, but should not
be assumed to be protective(115).
After ketamine administration, pupils dilate moderately, and
nystagmus occurs. Lacrimation and salivation are common, as is
increased skeletal muscle tone, often with coordinated but seemingly
purposeless movements of the arms, legs, trunk, and head. (111)
The duration of ketamine anesthesia is determined by the dose;
larger doses produce more prolonged anesthesia, and the concurrent use
of other anesthetics prolongs the time of emergence. Concomitant
administration of benzodiazepines, a common practice, may prolong the
effect of ketamine (116).
Analgesia occurs at considerably lower blood levels than loss of
L
W
VL
R
W VN

hP TW Peater). This means there is a considerable

period of postoperative analgesia after ketamine general anesthesia, and
subanesthetic doses can be used to produce analgesia. (111)
Ketamine increases CBF, which appears higher than the increase
in CMRO2 would mandate. With the increase in CBF and the
generalized increase in sympathetic nervous system response, there is an
increase in ICP after ketamine (117).

54

Review of literature

II) Cardiovascular effects:
Ketamine stimulates the cardiovascular system and is usually
associated with increases in blood pressure, heart rate, and cardiac output
and this is associated with increased work and myocardial oxygen
consumption. The healthy heart is able to increase oxygen supply by
increased cardiac output and decreased coronary vascular resistance, so
that coronary blood flow is appropriate for the increased oxygen
consumption. These hemodynamic changes are not dose-related.
The mechanism by which ketamine stimulates the circulatory
system remains enigmatic. It seems not to be a peripheral mechanism
such as baroreflex inhibition, but rather to be central. There is some
evidence that ketamine attenuates baroreceptor function via an effect on
NMDA receptors nucleus tractus solitaries. Ketamine also causes the
sympathoneuronal release of norepinephrine, which can be detected in
venous blood. Blockade of this effect is possible with barbiturates,
benzodiazepines, and droperidol. (111)
III) Respiratory effects:
Ketamine has minimal effects on the central respiratory drive as
reflected by an unaltered response to carbon dioxide. There can be a
transient (1 to 3 minutes) decrease in minute ventilation after the bolus
administration of an induction dose of Ketamine. Rarely large doses can
produce apnea.
Ketamine is a bronchial smooth muscle relaxant. When it is given
to patients with reactive airway disease and bronchospasm, pulmonary
compliance is improved. (111)

restrictive pericarditis(120)
II) Pain Management:
Ketamine administered in small doses decreases postoperative
analgesic consumption. Side effects, especially psychotomimetic effects,
were minimal, especially if a benzodiazepine also was administered (121).
III) Sedation:
Ketamine is particularly suitable for sedation of pediatric patients
as pediatric patients have fewer adverse emergence reactions than
adults(122).
Ketamine can be used as a supplement or an adjunct to regional
anesthesia, extending the usefulness of the primary (local anesthetic)
form of anesthesia (123).
Ketamine also may be considered for sedation of patients in a
critical care unit because of its combined sedative and analgesic
properties and favorable effects on hemodynamics (111).

Contraindications of ketamine (111):
Patients with increased ICP and with intracranial mass lesions
because it can increase ICP .
Patients with an open eye injury or other ophthalmologic disorders
because it can increase IOP.
As ketamine causes hypertension and tachycardia, with a
commensurate increase in myocardial oxygen consumption, it is
contraindicated as the sole anesthetic in patients with ischemic
heart disease. Also it is unwise to give ketamine to patients with
vascular aneurysms because of the possible sudden change in
arterial pressure.
Psychiatric disease, such as schizophrenia
History of adverse reaction to ketamine or one of its congeners.

57

Review of literature

When there is a possibility of postoperative delirium from other
causes (e.g., delirium tremens, possibility of head trauma), and a
ketamine-induced psychomimetic effect would confuse the
differential diagnosis.

Adverse reactions of ketamine:
Ketamine produces undesirable psychological reactions, which
occur during awakening from ketamine anesthesia and are termed
emergence reactions. The common manifestations of these reactions,
which vary in severity and classification, are vivid dreaming,
extracorporeal experiences (sense of floating out of body), hallucinations
and

illusions

experience)

(124)

(misinterpretation

of

a

real,

external

sensory

.

These incidents of dreaming and illusion are often associated with
excitement, confusion, euphoria, and fear. They occur in the first hour of
emergence and usually disappeared within one to several hours. It has
been postulated that the psychic emergence reactions occur secondary to
ketamine-induced depression of auditory and visual relay nuclei, leading
to misperception or misinterpretation of auditory and visual stimuli
(109). A clinically relevant range is probably 10% to 30% of adult
patients who receive ketamine as a sole or major part of the anesthetic
technique (111).
Another potential problem is the increased salivation which may
produce upper airway obstruction. Also it may contribute to or may
complicate further laryngospasm. In addition, although swallow, cough,
sneeze, and gag reflexes are relatively intact after ketamine

58

Review of literature

administration, there is evidence that silent aspiration can occur during
Ketamine anesthesia(111).

59

Review of literature

Tramadol

Figure 12:
12 Chemical structure of tramadol

(111)

Physiochemical characters of tramadol:
Tramadol is a centrally acting analgesic that acts at multiple sites,
providing moderate pain relief with low risk of respiratory depression,
tolerance and dependence. Tramadol is a synthetic 4-phenyl
4 phenyl-piperidine
analog of codeine (figure
igure 12).
12) Itt is administered as a racemic mixture of
two enantiomers.

Pharmacokinetics of tramadol:
Tramadol is rapidly and extensively absorbed after oral
administration, appearing in the plasma 15 to 45 minutes after
administration, with peak levels occurring after 2 h(125).
Tramadol has a high oral bioavailability (70i
(70 80%) that can
increase to 90i
100% with repeated dosage. Tramadol has a high tissue
affinity and is 20% bound to plasma proteins (126).

60

Review of literature

25-30% of the oral dose of tramadol is excreted unchanged in
urine. The main metabolic pathways of tramadol are N- and Odemethylation then conjugation of the O-demethylated metabolites. This
is done by hepatic cytochrome P450 system(127).
90% of tramadol and its metabolites are excreted in urine and the
remainder in faeces

(128)

. Both tramadol and its metabolites cumulate in

chronic renal disease and hepatic failure, and dose requirements may be
reduced by 50%. Conversely, the concurrent use of enzyme-inducing
agents (e.g. carbamazepine) may considerably reduce its plasma
concentration and analgesic efficacy (126).

Mechanism of action of tramadol:
Tramadol exerts its analgesic effect by a multi modal mechanism.
Tramadol possesses only a modest affinity for h-receptor and no affinity
(129)

In addition to its opioid actions, tramadol inhibits the neuronal
reuptake of norepinephrine and serotonin (5-HT). These monoamine
neurotransmitters are involved in the anti-nociceptive effects of
descending inhibitory pathways in the central nervous system(127).

Pharmacodynamics of tramadol:
Tramadol is a potent analgesic that is found effective in
providing analgesia superior to that of placebo when administered in its
oral or parentral forms (127).

61

Review of literature

Analgesic doses of tramadol produce no respiratory depression, in
part because of its non-opioid receptor-mediated actions(130), and have
minimal effects on gastrointestinal motor function(131).

Side effects of tramadol:
Tramadol is generally well tolerated; however, gastrointestinal and
nervous system side effects, in particular, lead to 19 to 30% of patients
discontinuing therapy(132).
Dizziness (26-33%), headache (18-32%), sedation (16-25%),
nausea (24-40%), vomiting (9-17%) and constipation (24-46%) are the
most common side-effects(125).
Side effects appear to be route- as well as dose-dependent, with
parenteral administration associated with more complications

(125)

. Some

authors suggested that side-effects can be decreased by beginning with a
low dose that is incremented to the target dose i.e. true rate effect, rather
than simply dosage related (133).

recommends 50 mg every 4 to 6 hours as needed for moderate pain. For
severe pain 100 mg is advocated, followed by 50 to100 mg every 6 hours
to a maximum of 400 mg in 24 h (300 mg/24 h in the elderly).
Epidural administration of preservative-free tramadol appears to
be safe and effective (134).

62

Review of literature

Tramadol may be an advantageous adjunct to regional anaesthesia.
Tramadol 100 mg added to mepivacaine 1% was shown to prolong the
duration of brachial plexus block by 54% compared with patients
receiving mepivacaine alone (135).
Tramadol 25-50 mg has a local anaesthetic effect after intradermal
injection (136), and significantly reduces the pain of propofol injection to a
similar degree to lignocaine 1% (137).

tramadol can contributes to the reduction in the dosage and thus side
effects of NSAID as well as drugs with a high dependency or tolerance
profile.

63

Aim of the work

2010

Aim of the work

Aim of the Work
This is a prospective randomized, comparative, placebo controlled
study in which the efficacy of each of midazolam, midazolam plus
ketamine, tramadol, and tramadol plus ketamine, for prophylaxis of postspinal shivering is evaluated and compared to each other.

65

Patients and
methods

2010

Patients and methods

Patients and Methods
After obtaining institutional approval and written consent from all
patients, this prospective, randomized, comparative and placebo
controlled study was carried out in Tanta University Hospital from
November 2009 to July 2010 on one hundred ASA status I and II
patients between the ages of 21- 60 years who were undergoing elective
orthopedic surgery under spinal anesthesia.
Exclusion criteria:
Patients

with

thyroid

diseases,

cardiopulmonary

diseases,

neuromuscular diseases or psychological disorders were excluded from
the study. Also patients on narcotics, sedatives, opioids, vasodilators,
antipyretics or any medication likely to alter thermoregulation, or with a
known history of drug abuse were excluded. Also we excluded patients
in a need for blood transfusion during surgery, patients with an initial
KWMa N NJ N1 ,)d
4W 0 d
4 JR
N
V

R N
L
N
V RWaWO

febrile illness, and patients with history of malignant hyperthermia.
Preoperative investigation:
Routine preoperative investigations including complete blood
picture, renal function tests, liver function tests and coagulation profile
were done for preoperative evaluation.
Anesthetic technique:
All patients didn't receive any pre-medication. On arrival to the
operating theatre, all patients had a venous cannula inserted. I.V fluids in

67

Patients and methods

NO
W

WOT
J
LJN
M R
VPNm WT R
WV NNR
VO N
MJ J JNWO

ml/kg/h over 30 minutes before spinal anesthesia then the rate was
reduced to 6 ml/kg/h. I.V. fluids were not warmed. The ambient
temperature was maintained at 22-&(d
4
All patients had spinal anesthesia where 15 mg hyperbaric
Bupivacaine 0.5% was instituted at either L3/L4 or L4/L5 using a 22 G
Quincke spinal needle under complete aseptic conditions. The patients
were allocated randomly to one of five groups:
Group C (n=20):

Received saline as a control.

Group M (n=20):

Received mR
MJ
b
WT
J )hPSP.

MJ
b
WT
J
Group MK (n=20): Received mR

)hPSP T ketamine

0.25 mg/kg.
Group T (n=20):

Received tramadol 0.5 mg/kg.

Group TK (n=20):

Received tramadol 0.25 mg/kg plus ketamine
0.25 mg/kg.

All of these drugs were diluted to volume of 5 ml and was given as
an I.V. bolus immediately after intrathecal injection. Supplemental
oxygen was given via a face mask at a rate of 5 L/min during the
operation. All patients were covered with one layer of surgical drapes
over the chest, thighs and calves during the operation and one cotton
blanket over the entire body after the operation.
After intrathecal injection the sensory and motor block were
assessed with a pinprick test every 5 minutes. When spinal anesthesia
was established the presence of shivering was observed and graded by
using a scale similar to that validated by Tsai and Chu (38) where:

68

Patients and methods

0 = No shivering.
1 = Piloerection or peripheral vasoconstriction but no visible
shivering.
2 = Muscular activity in only one muscle group.
3 = Muscular activity in more than one muscle group but not
generalized.
4 = Shivering all over the body.
This score was evaluated during surgery. If shivering occurred, it
was graded and recorded and if the grade was 3 or 4 after 15 minute
from the administration of the tested prophylactic drug, it was considered
severe shivering and rescue treatment in the form of I.V. 25 mg of
pethidine was given.
Heart rate, respiratory rate, mean arterial blood pressure, peripheral
oxygen saturation (SpO2) and tympanic membrane temperature were
recorded using standard noninvasive monitors at 10 minutes intervals
during the pre- and the post-anesthesia period.
The degree of sedation was assessed according to a five-point scale
where:
1 = Fully awake and oriented.
2 = Drowsy.
3 = Eye closed but responds to commands.
4 = Eye closed but responds to mild physical stimulation.
5 = Eye closed and not responding to mild physical stimulation.
Any other side effect was recorded and properly treated e.g.
hypotension, nausea, vomiting and hallucination.
69

Chicago, IL, USA).
Statistical presentation and analysis of this study was conducted,
using the mean, standard deviation (SD), analysis of variance (ANOVA)
test and Chi-

JN u
& N WNJ R
VNMR
O
O
NN
VL
NJ WVP NO
RN

groups as regard the parametric variables.
Categorial variables were analyzed using 5o2 Chi-

JN
Mu
&

test to determine the difference among the five groups, followed by a
series of 2o2 Fisher's exact test, Chi-

JN u
&N

VNGJ
a2

F2

test or Mann-Whitney test when appropriate for the intergroup
differences.
P-value < 0.05 was considered significant.

70

Results

2010

Results

Results
This study was conducted after patient approval and consent on
100 patients presented for orthopedic surgery using spinal anesthesia.
Part of the research was during anesthesia and surgery including clinical
data such as the heart rate, mean arterial blood pressure, peripheral O2
saturation, respiratory rate and core temperature.
The other part of the research was a trial to evaluate the
prophylactic use of Midazolam, Midazolam plus Ketamine, Tramadol
and Tramadol plus Ketamine on the incidence of post-spinal shivering,
where the patients were closely observed for detection of shivering and
its grade. Also the patients were closely monitored for detection of any
side effect. Our results were recorded in the following tables:

Table 6 shows patients' demographic data, duration of surgery
and ASA status:
The comparison of patients' demographic data showed that the
differences among the five groups were not statistically significant as
regard age (P-value was 0.126), weight (P-value was 0.951), BMI (Pvalue was 0.710) and sex (P-value was 0.899). Also there were no
statistically significant differences between the groups as regard ASA
status (P-value was 0.240) and duration of surgery (P-value was 0.096).
72

different from the base (P-value was 0.220, 0.548 and 0.973
respectively).

82

Results

Table 12 : Changes of the mean heart rate in the five groups
Heart Rate (HR)

ANOVA

Group C Group M Group MK Group T Group TK
Mean

91.75

93.10

92.95

91.10

92.55

SD

6.882

6.897

4.740

6.805

6.637

Mean

71.60

71.30

69.70

68.70

69.45

SD

4.593

4.824

3.585

4.485

3.677

Mean

73.60

74.15

72.35

72.20

73.05

SD

5.236

5.518

6.310

5.116

5.000

Mean

78.35

79.45

81.20

78.40

81.10

SD

5.008

5.395

3.412

5.384

4.254

Mean

89.75

89.90

90.50

89.40

90.60

SD

4.919

4.678

4.059

4.418

4.593

Mean

90.40

90.85

93.05

91.05

93.55

SD

3.899

4.966

4.466

4.571

3.620

Mean

90.70

89.40

91.25

89.95

92.60

SD

5.895

5.02

3.985

5.286

4.382

Base

10 minutes

20 minutes

30 minutes

40 minutes

50 minutes

60 minutes

Values are expressed as means and SD

83

F

P-value

0.345

0.847

1.712

0.154

0.457

0.767

1.724

0.151

0.252

0.908

2.145

0.081

1.247

0.297

Results

Group C

Group M

Group MK

Group T

Group TK

100
90
80
70
60
50
Base

10

20

30

40

50

60

Time in minutes

Figure 18: Changes of the mean heart rate in the five groups

Table 12 which is represented in figure 18 shows Changes of
the mean heart rate in the five groups:
There were no statistically significant differences among the five
groups as regard the mean heart rate value at each time interval from the
base value (P-value was 0.847) to 10, 20, 30, 40, 50 and 60 in the postanesthesia period (P-value was 0.154, 0.767, 0.151, 0.908, 0.081 and
0.297 respectively)

different from the base (P-value was 0.476, 0.795 and 0.850
respectively).

94

Results

Table 18 : Changes of the MAP rate in the five groups

Mean arterial blood pressure

ANOVA

Group C Group M Group MK Group T Group TK
Mean

94.75

95.95

95.7

94.5

96.4

SD

6.882

9.058

9.217

6.237

8.363

Mean

73.6

77.85

78.35

76.35

80.1

SD

4.593

9.566

8.671

10.489

7.759

Mean

73.6

78.4

78.85

78.75

79.25

SD

5.236

8.562

8.468

8.181

8.855

Mean

81.35

82.25

83.5

83.4

84.5

SD

5.008

9.02

7.647

8.022

7.437

Mean

92.75

94.2

94.75

93.35

95.65

SD

4.919

7.12

7.304

6.418

6.831

Mean

93.4

94.7

95.2

94.9

96.15

SD

3.899

6.522

6.396

5.946

5.575

Mean

93.7

94.45

96.35

93.5

96.6

SD

5.895

7.251

5.603

6.134

5.707

Base

10 minutes

20 minutes

30 minutes

40 minutes

50 minutes

60 minutes

Values are expressed as means and SD

95

F

P-value

0.202

0.937

1.664

0.165

1.739

0.148

0.522

0.720

0.603

0.661

0.596

0.666

1.137

0.344

Results

Group C

Group M

Group MK

Group T

Group TK

110
100
90
80
70
60
Base

10

20

30

40

50

60

Time in minutes

Figure 24: Changes of the MAP in the five groups

Table 18 which is represented in figure 24 shows Changes of
the MAP in the five groups:
There were no statistically significant differences among the five
groups as regard the mean MAP value at each time interval from the
base value (P-value was 0.937) to 10, 20, 30, 40, 50 and 60 of the postanesthesia period (P-value was 0.165, 0.148, 0.720, 0.661, 0.66 and
0.344 respectively).

Table 24 which is represented in figure 30 shows Changes of
the respiratory rate in the five groups:
There were no statistically significant differences among the five
groups as regard the mean respiratory rate value at each time interval
from the base value (P-value was 0.802) to 10, 20, 30, 40, 50 and 60 of
the post-anesthesia period (P-value was 0.244, 0.677, 0.169, 0.550, 0.966
and 0.175 respectively).

Table 30 : Changes of the SpO2 in the five groups
Peripheral O2 saturation (SpO2)

ANOVA

Group C Group M Group MK Group T Group TK
Mean

97.35

97.35

97.2

97.35

97.35

SD

1.226

0.813

1.361

1.137

1.089

Mean

96.95

96.9

97.3

97.1

97.2

SD

1.05

0.912

1.565

1.373

0.894

Mean

97

97.05

97.1

97.25

97.3

SD

0.918

1.099

1.281

2.209

1.174

Mean

97.95

97.65

97.4

97.85

97.5

SD

0.999

0.988

1.142

1.226

1.051

Mean

97.5

97.3

97.8

97.55

97.8

SD

0.889

1.129

0.894

1.146

1.105

Mean

97.25

97.4

97.45

97.5

97.25

SD

0.91

1.231

1.317

1.395

1.209

Mean

97

97.6

97.75

97.55

97.85

SD

0.973

0.883

0.85

1.317

1.137

Base

10 minutes

20 minutes

30 minutes

40 minutes

50 minutes

60 minutes

Values are expressed as means and SD

119

F

P-value

0.0693

0.991

0.396

0.811

0.168

0.954

0.905

0.465

0.843

0.501

0.177

0.950

1.986

0.103

Results

Group C

Group M

Group MK

Group T

Group TK

98
97.5
97
96.5
96
95.5
95
Base

10

20

30

40

50

60

Time in minutes

Figure 36: Changes of the SpO2 in the five groups

Table 30 which is represented in figure 36 shows changes of
the SpO2 in the five groups:
There were no statistically significant differences among the five
groups as regard the mean SpO2 value at each time interval from the base
value (P-value was 0.991) to 10, 20, 30, 40, 50 and 60 of the postanesthesia period (P-value was 0.811, 0.954, 0.465, 0.501, 0.950 and
0.103 respectively)

Figure 42: Changes of tympanic membrane temperature in the five groups

Table 36 which is represented in figure 42 shows changes of
the tympanic membrane temperature in the five groups:
There were statistically insignificant differences among the five
groups as regard the mean tympanic membrane temperature base value
(P-value = 0.067) while there were statistically significant differences
J WVP NO
RNPW

two groups at each time interval. The test revealed that:
The change in the mean tympanic membrane temperature in
Group MK was statistically significant (P-value was < 0.05) when
compared with Group C, Group M and Group T at all time intervals.

132

Results

However that change in temperature was not statistically significant (Pvalue was > 0.05) when compared with Group TK at any time.
The change in the mean tympanic membrane temperature in
Group TK was statistically significant (P-value was < 0.05) when
compared with group C and group M at all time intervals. However that
change in temperature was statistically significant (P-value was < 0.05)
when compared with Group T till 20 minutes of the post-anesthesia
period, then at 30, 40, 50 and 60 minutes the change in temperature was
statistically insignificant (P-value was > 0.05).
The change in the mean tympanic membrane temperature in group
T was not statistically significant when compared with group C and
group M at any time of the post-anesthesia period (P-value was > 0.05).
The change in the mean temperature in Group M was not
statistically significant (P-value > 0.05) when compared with Group C at
any time.

133

Results

Shivering:
Table 37 : Overall incidence of shivering in the five groups
Group C
(n=20)

Group

Group

M

MK

(n=20)

(n=20)

Group T

Group TK

(n=20)

(n=20)

11 (55)

9 (45)

1 (5)*

6 (30)

3 (15)

Non-Shiverers

9 (45)

11 (55)

19 (95)

14 (70)

17 (85)

Values are expressed as number of patients (%)
* Significant in comparison with group C, group M and group T (P-value < 0.05).
gSignificant in comparison with group C and group M (P-value < 0.05).

Group M

Group MK

Group T

Group TK

20
18
16
14
12
10
8
6
4
2
0
Shiverers

Non-Shiverers

Figure 43: Overall incidence of shivering in the five groups

134

P

g

Shiverers

Group C

Chi-square

16.190

0.003

Results

In table 37 which is represented in figure 43 the incidence of
shivering in the post-anesthesia period in the five studied groups is
compared:
There was significant difference among the five Groups (P-value
J

CW

TRT
N&
o&7R N NJ
LN

NNMW
VN WL
W JN

each two groups.
Group MK showed significant low incidence of shivering (5%)
when compared with Group C (55%), Group M (45%) and Group T
(30%) (P-value was < 0.001, 0.004 and 0.046 respectively) that
incidence is less than that occurred in Group TK (15%) but it was not
statistically significant (P-value was 0.302).
Group TK also showed a statistically significant lower incidence
of shivering when compared to Group C and Group M (P-value was
0.009 and 0.041 respectively) but when compared with Group T, that
less incidence of shivering was not statistically significant (P-value was
0.225).
The incidence of shivering was less in the Group T than Group C
and Group M but was not statistically significant (P-value was 0.100 and
0.257 respectively).
There was no statistically significant difference between the group
C and group M (P = 0.376).

135

Results

Table 38 : Shivering score of all patients in the five groups
Group

Group

Group

Group

Group

C

M

MK

T

TK

(n=20)

(n=20)

(n=20)

(n=20)

(n=20)

0

9 (45)

11 (55)

19 (95)

14 (70)

17 (85)

16.190

0.003

1

3 (15)

4 (20)

0 (0)

1 (5)

0 (0)

8.967

0.062

2

2 (10)

3 (15)

1 (5)

4 (20)

2 (10)

2.462

0.651

3

5 (25)

2 (10)

0 (0)

1 (5)

1 (5)

9.035

0.060

4

1 (5)

0 (0)

0 (0)

0 (0)

0 (0)

4.040

0.401

Shivering
Score

Chi-square
P

Values are expressed as number of patients (%)

Group C

Group M

Group MK

Group T

Group TK

Score 2

Score 3

Score 4

20
18
16
14
12
10
8
6
4
2
0
Score 0

Score 1

Figure 44: : Shivering score of all patients in the five groups

136

Results

In the table 38 which is represented in figure 44 the number of
patients suffered from each grade of shivering was compared:
No statistically significant differences were found among the groups as
regard the grade of shivering.

137

Results

Table 39 : Incidence of severe shivering (score

Shivering
score

3) in the five groups

Group

Group

Group

Group

M

MK

T

TK

(n=20)

(n=20)

(n=20)

(n=20)

6 (30)

2 (10)

0 (0)*

1 (5)*

1 (5)*

14 (70)

18 (90)

20 (100)

19 (95)

19 (95)

Group C
(n=20)

Chi-square
P

12.222 0.016

<3

Values are expressed as number of patients (%)
* Significant in comparison with group C (P-value < 0.05).

Group C

Group M

Group MK

Group T

Group TK

20
18
16
14
12
10
8
6
4
2
0
3

Score < 3

Figure 45: Incidence of severe shivering (score

3) in the five groups

The table 39 which is represented in figure 45 shows incidence
of severe shivering (score f3):
There was significant difference among the groups (P-value was
CW

TRT
N&o&7R N NJ
LN

two groups.

138

NNMW
VN WL
W JNN
J
L

Results

No patients showed severe shivering in Group MK that was
statistically significant when compared with Group C where 6 patients
(30%) suffered from severe shivering (P-value was 0.010). When
comparing Group MK with Group M (10%), Group T (5%) and Group
TK (5%), no statistically significant differences were found (P-value was
0.243, 0.500 and 0.500 respectively).
The incidence of severe shivering in Group T was equal with that
of Group TK and low when compared with group C that was statistically
significant (P-value was 0.045 for each group).
The differences between Group C and Group M was not
statistically significant (P-value was 0.117) in spite of the lower
incidence in group M.
Also the differences between group M and each of group T and
group TK were not statistically significant (P-value was 0.500 for each
group).

139

Results

Complications:
Table 40 : Incidence of complications in the five groups
Group C

Group M

Group MK

Group T

Group TK

(n=20)

(n=20)

(n=20)

(n=20)

(n=20)

Hypotension

4 (20)

3 (15)

1 (5)

3 (15)

2 (10)

2.299

0.681

Hallucinations

0 (0)

0 (0)

1 (5)

0 (0)

2 (10)

5.498

0.240

Nausea

3 (15)

4 (20)

5 (25)

6 (30)

5 (25)

1.468

0.832

Vomiting

1 (5)

0 (0)

0 (0)

2 (10)

1 (5)

3.646

0.456

Complication

Chi-square
P

Values are expressed as number of patients (%)

Group C

Group M

Group MK

Group T

Group TK

8
7
6
5
4
3
2
1
0
Hypotension

Hallucinations

Nausea

Figure 46: Incidence of complications in the five groups

140

Vomiting

Results

In the table 40 which is represented in figure 46 the numbers of
patients suffered from complications are enlisted:
Statistical analysis showed that no significant differences among
the groups as regard the incidence of hypotension, hallucinations, nausea
and vomiting (P-value was0.681, 0.240, 0.832 and 0.456 respectively).

141

Results

Sedation:
Table 41 : Sedation score of all patients in the five groups
Group

In table 41 which is represented in figure 47 the numbers (and
percent) of patients suffered from each grade of sedation were
compared:
Statistically significant differences were found among the groups
as regard each sedation grade except for grade 5 where no test was done
as there were no patients found to have grade 5 sedation.
So further testing was done using Mann-Whitney Test to compare
the median sedation score between each two groups.
The median sedation score was significantly higher in Group M
(3) than Group C (1), Group MK (2), Group T (1) and Group TK (1.5)
where P-value was < 0.001, 0.027, 0.001 and 0.001 respectively.
Group MK showed statistically significant higher median sedation
score than Group C and Group T (P-value was < 0.001 and 0.009
respectively) but not statistically different when compared with group
TK (P-value was 0.167)
No statistically significant difference was found between group T
and group TK though the higher median sedation score in group TK as
P-value was 0.153.

143

Discussion

2010

Discussion

Discussion
Post-anesthetic shivering is a common complication of regional
anesthesia affecting up to 60% of patients

increase tissue oxygen demand by as much as 500%. This may be
deleterious in patients with impaired cardiovascular reserve or a limited
respiratory capacity(9). Shivering also may interfere with the monitoring
of patients by causing artifacts of the ECG, blood pressure, and pulse
oximetry recording (10).
Various opioid and non-opioid agents were used to prevent and
treat shivering, but they are not without side effects like hypotension,
hypertension, respiratory depression, nausea etc. Also a variety of
physical agents (radiant heat, space blanket etc) were also used to
prevent perioperative shivering, but those were cumbersome and with
limited success (11) .
The aim of this prospective, randomized, comparative, placebo
controlled study is to evaluate the efficacy of each of midazolam,
midazolam plus ketamine, tramadol, and tramadol plus ketamine, for
prophylaxis of post-spinal shivering.
In the present study post-spinal shivering incidence was 55% of
the patients (11/20) in the control group (Group C) this is similar to the
incidence of shivering in the control group of previous studies by
Honarmand, et al(3) and Sagir, et al (12).

145

Discussion

Honarmand, et al compared the prophylactic use of midazolam,
ketamine, ketamine plus midazolam and placebo for prevention of
shivering during regional anesthesia, and found that the shivering
incidence was 60% in the control group(3). Also, Sagir, et al compared
placebo, ketamine, granisetron, and a combination of ketamine and
granisetron for the prevention of shivering caused by regional anesthesia,
and found that the incidence of shivering was 55% in the control
group(12).
This high incidence of shivering observed in the control group of
the present study was consistent with the significant decrease of the core
temperature observed in the patient of this group during the postanesthesia period.
Core hypothermia during regional anesthesia is common

(141)

and

can be nearly as severe as that observed during general anesthesia(142).
There are three principal reasons for hypothermia under spinal
anesthesia. First, spinal anesthesia leads to an internal redistribution of
heat from the core to the peripheral compartment(44). Secondly, with loss
of thermoregulatory vasoconstriction below the level of the spinal block,
there is increased heat loss from body surfaces. Lastly, there is altered
thermoregulation under spinal anesthesia charactNR
b
N
M Ka J )d
4
decrease in vasoconstriction and shivering thresholds(143).
However, in the study of Kelsaka, et al who compared the
efficacy of ondansetron and meperidine in the prevention of shivering
after spinal anesthesia, they reported that shivering incidence was 36%
of the control group (144). This lower incidence of shivering was probably
due to a number of reasons: first, in contrast to the present study, all
146

shivering was evaluated by observing the pectoralis major muscles for
fasciculations for more than 10 s. In the current study, shivering was
graded using a scale which considered piloerection or peripheral
vasoconstriction, but no visible shivering as Grade 1.
GABA receptors have been demonstrated in the spinal cord.
GABAergic neurones mediate presynaptic inhibition, suppressing signals
from

muscle

and

cutaneous

receptors.

Midazolam and

other

benzodiazepines, which decrease GABA reuptake from synaptic clefts,
have been found to reduce repetitive firing in response to depolarizing
pulses in spinal cord neurons

(85)

. Such inhibitory functions of

benzodiazepines in the spinal cord may be responsible for inhibiting the
conduction of afferent impulses from cold receptors to the higher
centers, thereby suppressing shivering (3).
However, in the midazolam group (Group M) of the current study
shivering occurred in 45% of patients (9/20) which was lower but,
statistically insignificant, when compared with the control group (Group
C). Also, the incidence of severe shivering (score f

J VW

significantly different than the control group (Group C).
This incidence is similar with that found by Honarmand, et al
where the shivering incidence was 50% of the midazolam group (3).
Kurz, et al studied the effect of midazolam on thermoregulation
and found that reduction in heat production after administration of
midazolam is less than that after induction of anesthesia with clinical

147

Discussion

doses of volatile anesthetics, propofol, and opioids. Also, they reported
that midazolam, even in plasma concentrations far exceeding those used
routinely, produces minimal impairment of thermoregulatory control(145).
This explains the lower incidence of shivering observed in our patients
receiving midazolam. However, in another study by Grover, et al, they
showed that administration of midazolam towards the end of the
anesthetic procedure doesn't prevent shivering but it subsides earlier in
the postoperative period (146).
This incidence was consistent with the failure of midazolam to
prevent or minimize the core hypothermia as the decrease in the core
temperature in Group M during the post-anesthesia period was
insignificantly different from that occurred in the control group. This can
be explained by its action of inhibiting the tonic thermoregulatory
vasoconstriction.(146)
The incidence of shivering in the tramadol group (Group T) of the
present study was 30% of the patients (6/20) which was significantly
lower than that of the control group (Group C). In addition, tramadol
significantly lowered the incidence of severe shivering when compared
with Group C.
This incidence coincides with previous studies like that of
Atashkhoyi, et al who investigated the effect of tramadol for prevention
of shivering after spinal anesthesia for cesarean section and they reported
that shivering occurred in 28.57% of the patients in the tramadol
group(7). Also, Bilotta, et al who investigated the effect of nefopam and
tramadol on shivering during neuraxial anesthesia, had similar incidence

148

Discussion

of shivering in the Tramadol group (24%)

(147)

. On the other hand,

Talakoub, et al who used tramadol for prevention of shivering following
spinal anesthesia, reported that the incidence of shivering was only 3%
in the tramadol group

(5)

but this much lower incidence may be because

they recorded only shivering grade f3.
Similar to its analgesic effect, the anti-shivering effect of tramadol
is most likely mediated by multimodal mechanism. Tramadol possesses
only a modest affinity for h-receptor and no affinity for q
-J
VMt-opioid
receptors

(129)

. In addition to its opioid actions, tramadol inhibits the

neuronal reuptake of norepinephrine and serotonin (5-HT). These
monoamine neurotransmitters are involved in the anti-shivering effects
of descending inhibitory pathways in the spinal cord(127).
In the midazolam plus ketamine group (Group MK) the incidence
of shivering was 5% (1/20) of the patients. This incidence was not only
lower than Group C, but also was lower than other groups including the
Group M. This notice coincides with the findings by Honarmand, et al
where the incidence of shivering in their midazolam ketamine group was
3.3% (3).
Similarly in the tramadol plus ketamine group (Group TK) the
incidence of shivering was 15%

(3/20) of patients which was

significantly lower than each of Group C and Group T. Searching the
famous scientific databases of medical journals like PubMed and
ScienceDirect didn't reveal a study in which this combination was used
for prevention or treatment of shivering. So further studies on this
combination should be performed to confirm or deny the results of the
current study.
149

Discussion

These findings confirm the reported anti-shivering effect of
ketamine by Honarmand, et al

(3)

and Sagir, et al

(12)

where ketamine

significantly decreased the incidence of shivering whenever it was used
in their studies. Also, Sharma, et al(148) reported that ketamine has been
shown to prevent shivering in patients undergoing regional anesthesia.
This was consistent with the observation that there were no
significant changes in core temperature in Group MK and Group TK of
the current study. This coincides with the findings by Kinoshita, et al
who showed that during spinal anesthesia, infusion of low-dose ketamine
prevents decreases in the body temperature of patients sedated with
propofol(149).
Ketamine

probably

controls

shivering

by

N WPN
VNR N
R N Ka J
LR
W
VW
V N aW J
T
J

non-shivering
W Ka N r-

adrenergic effect of norepinephrine(148). Thus, ketamine causes
sympathetic stimulation and vasoconstriction in patients at risk of
hypothermia. This effect of ketamine is in contrast to that of midazolam
which reduces core temperature by inhibiting tonic thermoregulatory
vasoconstriction (146).
It is clear from the present study that adding ketamine to
midazolam or tramadol enhanced their anti-shivering effect. This
suggests that ketamine has a synergistic anti-shivering effect when
combined with any of the two drugs. So, further studies are needed to
find out the exact mechanism of interaction.
During spinal and local anesthesia, intravenous sedation and
hypnotic drugs are often administered to increase patient comfort, to

150

Discussion

maintain cardio respiratory stability, to improve surgical condition and to
prevent recall of unpleasant events during surgery (150).
The median sedation score was significantly higher in Group M
than Group C, Group MK, Group T and Group TK. Group MK showed
statistically significant higher median sedation score than Group C and
Group T but not statistically different when compared with group TK.
No statistically significant difference was found between group T and
group TK. In this connection, the patients of Group M and Group MK
have more preoperative comfort than other groups.
The sympathetic blockade produced by spinal anesthesia induces
hemodynamic changes. Hypotension and bradycardia are the most
common side effects seen with spinal anesthesia

(151, 152)

. Carpenter , et

al reported an incidence of hypotension of 33% of the

patients

undergoing surgery under spinal anesthesia (18). In the present study the
incidence of hypotension was 20% of the patients in the control group.
This lower incidence than that of Carpenter , et al may be due to the
difference in the patient group where the present study was restricted to
patients scheduled for elective orthopedic surgery excluding any patient
needing special fluid management or blood transfusion. This is
supported by the similar incidence of hypotension in the control group in
the study of Honarmand, et al (23.3%) which was conducted on a
patients group similar to that in the present study (3).
Sympathetic blockade and unopposed vagal activity cause
increased peristalsis of the gastrointestinal tract, which leads to nausea.
Accordingly, atropine is useful for treating nausea after high spinal
blockade

(25, 147)

. Nausea and vomiting occur after spinal anesthesia
151

Discussion

approximately 20% of the time (18) which is consistent with the incidence
of nausea and vomiting in the control group of the present study (15%
and 5% respectively).
In the groups where midazolam was used (Group M and Group
MK), no significant difference between each of them and the control
group as regard the hypotension, nausea and vomiting incidence. This
coincides with the findings of Honarmand, et al(3) and support the
previous findings of Forster, et al

(89)

that midazolam produces minimal

hemodynamic changes.
Similarly, in the groups where tramadol was used (Group T and
Group TK), no significant difference between each of them and the
control group as regard the hypotension, nausea and vomiting incidence.
This coincides with the findings of previous studies by Atashkhoyi, et
al(7) and Bilotta, et al (147).
No significant difference between the control group and each of
the ketamine groups (Group MK and group TK) as regard the
hypotension, nausea and vomiting incidence. This coincides with the
findings of previous studies by Honarmand, et al (3), Sagir, et al (12) .
Ketamine produces undesirable psychological reactions termed
emergence reactions. The common manifestations are vivid dreaming,
extracorporeal experiences (sense of floating out of body), hallucinations
and

illusions

(misinterpretation

of

a

real,

external

sensory

experience)(124). However in the current study the incidence of
hallucinations in patients receiving ketamine was very low (10% in
Group TK and 5% in Group MK) that was not significant when

152

Discussion

compared to the control group. This can be explained by the use of low
dose of ketamine in the present study (0.25 mg/kg). This is supported by
previous studies by Honarmand, et al(3), Sagir, et al

(12)

where similar

dose of ketamine was used with no incidence of hallucinations.
From all the observation in the present study it can be inferred that
I.V. mR
MJ
b
W
T
J

Summary and conclusion
Post-anesthetic shivering is spontaneous, involuntary, rhythmic,
oscillating, tremor-like muscle hyperactivity that increases metabolic
heat production up to 600% after general or regional anesthesia.
Regional anesthesia is associated with post-anesthetic shivering in
up to 60% of patients. Post-anesthetic shivering may cause major
discomfort to patients, and aggravate wound pain by stretching incisions
and increase intracranial and intraocular pressure. Also it may increase
tissue oxygen demand by as much as 500% and accompanied by
increases in minute ventilation and cardiac output to maintain aerobic
metabolism. This may be deleterious in patients with impaired
cardiovascular reserve or a limited respiratory capacity. Shivering also
may interfere with the monitoring of patients by causing artifacts of the
ECG, blood pressure, and pulse oximetry recording.
Shivering may be normal thermoregulatory mechanism in
response to core hypothermia. Core Hypothermia during regional
anesthesia is common and can be nearly as severe as that observed
during general anesthesia. There are three principal reasons for
hypothermia under spinal anesthesia. First, spinal anesthesia leads to an
internal redistribution of heat from the core to the peripheral
compartment. Secondly, with loss of thermoregulatory vasoconstriction
below the level of the spinal block, there is increased heat loss from
body surfaces. Lastly, there is altered thermoregulation under spinal
anesthesia chJJ
LNR
b
N
MKaJ )d
4 MN
LN
JNR
V JWL
WV R
LR
W
VJ
V
M

155

Summary & conclusion

shivering thresholds. However, non- thermoregulatory shivering also
occurs in normothermic patients.
Various opioid and non-opioid agents were used to prevent and
treat shivering, but they are not without side effects like hypotension,
hypertension, respiratory depression, nausea etc. A variety of physical
agents (radiant heat, space blanket etc) were also used to prevent
perioperative shivering, but those were cumbersome and with limited
success.
In this prospective, randomized, comparative, placebo controlled
study, the efficacy of each of Midazolam, Midazolam plus Ketamine,
Tramadol, and Tramadol plus Ketamine, for prophylaxis of post-spinal
shivering was evaluated and compared to each other
100 ASA I and II patients between the ages of 21- 60 years who
were undergoing elective orthopedic surgery under spinal anesthesia
were allocated randomly to one of five groups:
Group C (n=20):

Received saline as a control.

Group M (n=20):

Received midazolam 75 hPSP.

MJ
b
WT
J
Group MK (n=20): Received mR

)hPSP T ketamine

0.25 mg/kg.
Group T (n=20):

Received tramadol 0.5 mg/kg.

Group TK (n=20):

Received tramadol 0.25 mg/kg plus ketamine
0.25 mg/kg.

All of these drugs were diluted to volume of 5 ml and was given
as an I.V. bolus immediately after intrathecal injection.

156

Summary & conclusion

Shivering was observed and graded by using the following scale:
0

=

No shivering.

1

=

Piloerection or peripheral vasoconstriction but no
visible shivering.

2

=

Muscular activity in only one muscle group.

3

=

Muscular activity in more than one muscle group but
not generalized.

4

=

Shivering all over the body.

In the present study, post-spinal shivering occurred in 55% of
patients of Group C. This high incidence of shivering was consistent
with the significant decrease of the core temperature observed in the
patient of this group.
In Group M shivering occurred in 45% of patients which was
lower (although, statistically insignificant) when compared with the
Group C. Also the incidence of severe shivering (score f

J VW

significantly different in both groups. This incidence was consistent with
the failure of midazolam to prevent or minimize the core hypothermia as
the change in the core temperature in Group M was insignificant when
compared with the Group C.
The incidence of shivering in Group T was 30% of patients which
was significantly lower than that of the control Group C. However, the
change in the core temperature wasn't significantly different from that of
Group C. In addition, Tramadol significantly lowered the incidence of
sever shivering when compared with Group C

157

Summary & conclusion

Adding low dose ketamine to midazolam or tramadol enhanced
their anti-shivering effect. When low dose ketamine was added to
midazolam even with half of its dose of in group M the incidence is
lowered to 5% in Group MK. Similarly when low dose ketamine was
added to tramadol even with half of its dose of in group T the incidence
is lowered to 15% of patients in Group TK.
This was consistent with the observation that there were no
significant changes in core temperature in each of Group MK and Group
TK.
No statistically significant differences were found among the five
groups as regard the incidence of complications i.e. hypotension,
hallucinations, nausea and vomiting.